2-anilino-4-(heterocyclic)amino-pyrimidines

ABSTRACT

The present invention relates to 2-arylamino-4-(heterocyclic)aminopyrimidines inhibitors which are inhibitors and therefore inhibit Protein Kinase C-alpha (PKC-α). The PKC-α inhibitors of the present invention are important for improving myocardial intracellular calcium cycling, resulting in improved myocardial contraction and relaxation performance and thereby slowing the progression of heart failure. The present invention further relates to compositions comprising said 2-arylamino-4-(heterocyclic)amino-pyrimidines and to methods for controlling, abating, or otherwise slowing the progression of heart failure.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 11/762,394 filed Jun. 13, 2007, which claims benefit of U.S. provisional application No. 60/813,956, filed Jun. 15, 2006, the entirety of which is incorporated herewith by reference.

FIELD OF THE INVENTION

The present invention relates to 2-arylamino-4-(heterocyclic)aminopyrimidines which are inhibitors of Protein Kinase C-alpha (PKC-α). The PKC-α inhibitors of the present invention are important for improving myocardial intracellular calcium cycling, resulting in improved myocardial contraction and relaxation performance and thereby slowing the progression of heart failure. The present invention further relates to compositions comprising said 2-arylamino-4-(heterocyclic)amino-pyrimidines and to methods for controlling, abating, or otherwise slowing the progression of heart failure.

BACKGROUND OF THE INVENTION

Many biologically active substances, for example, hormones, neurotransmitters and peptides are known to exert functions via intracellular mediators such as, cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), diacylglycerol (DAG) and calcium. In many cases, these mediators activate or inactivate intracellular kinases or phosphatases that are important in protein phosphorylation/dephosphorylation, and thus play important roles in regulating cellular processes and functions. The protein kinase C (PKC) family of calcium and/or lipid-activated serine-threonine kinases function downstream of nearly all membrane-associated signal transduction pathways.¹ Approximately 12 different isozymes comprise the PKC family, which are broadly classified by their activation characteristics. The conventional PKC isozymes (PKCα, βI, βII, and γ) are calcium- and lipid-activated, while the novel isozymes (ε, θ, η, and δ) and atypical isozymes (ζ, ι, υ, and μ) are calcium independent but activated by distinct lipids.² For example, stimulation of Gαq-coupled G-protein coupled receptors (GPCR) can activate phospholipase C (PLC) which in turn mediates hydrolysis of inositol phospholipids resulting in the generation of inositol 1,4,5-triphosphate (IP₃) and DAG. IP₃ and DAG can activate the different isoforms of PKC by mobilizing calcium (calcium sensitive enzymes) or by directly activating PKC, respectively. Once activated, PKC isozymes translocate to discrete subcellular locations through direct interactions with docking proteins termed RACKs (Receptor for Activated C Kinases), which permit specific substrate recognition and subsequent signal transduction.³

Alterations in PKC activity has been suggested to contribute to human diseases, inter alia, diabetes, numerous forms of cancer, microalbinuria, endothelial dysfunction, cerebrovascular disease, stroke, coronary heart disease, cardiovascular disease and sequela (e.g. arrhythmia, sudden death, increased infarct size, congestive heart failure, angina), myocardial ischemic states, hypertension, lipid disorders, ischemia-reperfusion injury, atherosclerosis, peripheral artery/vascular disease, microvascular complications of diabetes (neuropathy, nephropathy, retinopathy), restenosis, renal disease, blood coagulation disorders, inflammatory diseases and heart failure and inhibition of PKC in these settings could be used to treat or prevent human disease. Lending support to the modulation of PKC in cardiac disease, PKC activation has been associated with cardiac hypertrophy, dilated cardiomyopathy, ischemic injury and mitogen stimulation.

Heart disease is the leading cause of death in industrialized nations. Historically heart failure (HF) has been a product of hypertension, coronary heart disease, genetic disorders, valvular deformities, diabetes or cardiomyopathy. While the root cause of heart failure is multifaceted, it uniformly is marked by impaired diastolic and/or systolic function and can be accompanied by chamber enlargement which ultimately manifest in symptomatic heart failure (fatigue, pulmonary edema, circulatory congestion, etc.)

The risk of death due to heart failure is 5-10% annually in patients with mild symptoms of heart failure, and increases to 30-40% annually in patients with advanced heart failure, with a 50% overall mortality rate at 5 years. The current mainstays of heart failure therapy are drugs that act on the renin-angiotensin-aldosterone system (ACEI, ARB, aldosterone inhibitor), diuretics, digoxin and β-adrenergic receptor blockers. Despite the fact that multiple drug classes are used to treat heart failure patients, new cases of heart failure are growing at over 10% per year.

Patients with acute decompensated heart failure (ADHF) are a treatment challenge to physicians and can present with volume overload and/or diminished cardiac output. Initial treatments for ADHF patients include intravenous diuretics, vasodilators, natriuretic peptides and inotropic agents. Despite the widespread use of these agents, long-term safety and benefit of these drugs have been questioned. In the case of inotropes, drugs that increase cardiac output and cardiac contractility without increasing myocardial oxygen consumption or heart rate are desirous. Despite the available treatments for patients with ADHF, hospital readmission rates are approximately 50% within 6 months and mortality is approximately 20-40% at 1 year.

The primary function of the heart is to generate and sustain an arterial blood pressure necessary to provide adequate perfusion of organs. It has, therefore, become an area of intense investigation to decipher the mechanism(s) which initiate and contribute to the development of heart failure rather than relying on a means for treating the symptoms of heart failure alone. At the cardiomyocyte (cardiac contractile cells) level, impaired calcium cycling is a hallmark of heart failure as is the basis of contractile abnormalities. Calcium plays a key role in regulating kinases, phosphatases and transcription factors believed to influence the remodeling process indicating that both acute and sustained alterations in intracellular calcium levels may have profound effect on cardiac function and remodeling (i.e., changes in wall thickness or chamber volume). This theory would support the proposition that the development of new therapies addressing the slowing and preventing of the disease progression, would be perhaps more effective against heart failure than palliation of heart failure.

Therefore, there is a limited means to treat patients with various forms and stages of heart failure and there is incentive to develop novel, safe and effective treatments to prevent or treat patients with symptoms of heart failure, acute exacerbation of heart failure and chronic heart failure and other cardiovascular diseases. An agent that has benefits in the treating acute exacerbations of heart failure as well as treating chronic heart failure is desirous.

-   1. Molkentin et al. (2001) Annu. Rev. Physiol. 63:391-426. -   2. Dempsey et al. (2000) Am. J. Physiol. Lung Mol. Physiol.     279:247-251. -   3. Mochly-Rosen, D. (1995) Science 268:247-251.

SUMMARY OF THE INVENTION

The present invention meets the aforementioned needs in that it has been found that certain 2-arylamino-4-(heterocyclic)aminopyrimidines are effective for inhibiting Protein Kinase C-alpha (PKC-α) thereby improving myocardial contraction and relaxation performance and slowing the progression of heart failure.

The present invention encompasses four major aspects each of which have their own separate categories, aspects, iterations, and specific iterative examples. The major aspects of the present invention include:

-   -   i) novel compositions of matter which are effective in         inhibiting PKC-α;     -   ii) compositions or pharmaceutical compositions (matrices)         comprising said compositions of matter;     -   iii) methods for treating, preventing, controlling, abating, or         alleviating one or more of the causes of progressive heart         failure which is affected by administration of a PKC-α         antagonist, whether administered alone or in a composition or         within a pharmaceutical composition (matrix); and     -   iv) a process for preparing the PKC-α inhibitors of the present         invention.

The first aspect of the present invention as a whole, relates to compounds, which include all enantiomeric and diastereomeric forms and pharmaceutically acceptable salts thereof, said compounds having the formula:

-   -   wherein R is a substituted or unsubstituted heterocyclic unit         containing from 3 to 7 atoms;     -   L is a linking group having the formula:

—[C(R^(4a)R^(4b))]_(n)—

-   -   each R^(4a) and R^(4b) is independently chosen from:     -   i) hydrogen; or     -   ii) C₁-C₄ linear, branched, or cyclic alkyl;     -   the index n is from 0 to 4; and     -   R¹ is substituted or unsubstituted phenyl having the formula:

-   -   R⁵ is hydrogen or one or more independently chosen substitutes         for hydrogen.

The second major aspect of the present invention relates to compositions comprising:

-   -   a) an effective amount of one or more compounds according to the         present invention; and     -   b) one or more acceptable excipients.

The third major aspect of the present invention relates to methods of use. As described herein below, the PKC-α inhibitors of the present invention are important for improving myocardial contraction and relaxation performance and thereby slowing the progression of heart failure and their administration to humans is, therefore, an effective treatment for humans suffering from acute heart failure.

The fourth major aspect of the present invention relates to a process for preparing the PKC-α inhibitors of the present invention.

These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (° C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention addresses several unmet medical needs, inter alia:

-   -   1) improving cardiac contraction/relaxation parameters in heart         failure patients, leading to reduction of symptoms; and     -   2) attenuating adverse cardiac remodeling in heart failure         patients, ultimately providing prolonged patient survival.

These and other unmet medical needs are resolved by the PKC-α inhibitors of the present invention, which are capable of blocking Protein Kinase C-alpha from impairing sarcoplasmic reticulum Ca²⁺ uptake. By providing heart failure patients with a PKC-α inhibitor, it is believed the patients will derive an improvement in cardiac function, thus resulting in improved myocardial contraction and relaxation performance and could result in slowing the progression to heart failure.

The following chemical hierarchy is used throughout the specification to describe and enable the scope of the present invention and to particularly point out and distinctly claim the units which comprise the compounds of the present invention. The term “hydrocarbyl” stands for any carbon atom-based unit (organic molecule), said units optionally containing one or more organic functional group, including inorganic atoms comprising salts, inter alia, carboxylate salts, quaternary ammonium salts. Within the broad meaning of the term “hydrocarbyl” are the classes “acyclic hydrocarbyl” and “cyclic hydrocarbyl” which terms are used to divide hydrocarbyl units into cyclic and non-cyclic classes.

As it relates to the following definitions, “cyclic hydrocarbyl” units may comprise only carbon atoms in the ring (hydrocarbyl and aryl rings) or may comprise one or more heteroatoms in the ring (heterocyclic and heteroaryl). For “hydrocarbyl” rings the lowest number of carbon atoms in a ring are 3 carbon atoms; cyclopropyl. For “aryl” rings the lowest number of carbon atoms in a ring are 6 carbon atoms; phenyl. For “heterocyclic” rings the lowest number of carbon atoms in a ring is 1 carbon atom; diazirinyl, epoxy. For “heteroaryl” rings the lowest number of carbon atoms in a ring is 1 carbon atom; 1,2,3,4-tetrazolyl.

A. Substituted and Unsubstituted C₁-C₂₀ Acyclic Hydrocarbyl:

For the purposes of the present invention the term “substituted and unsubstituted C₁-C₂₀ acyclic hydrocarbyl” encompasses 3 categories of units:

-   1) C₁-C₂₀ linear or branched alkyl, non-limiting examples of which     include, methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃),     n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), tert-butyl (C₄), and     the like; substituted C₁-C₂₀ linear or branched alkyl, non-limiting     examples of which includes, hydroxymethyl (C₁), chloromethyl (C₁),     trifluoromethyl (C₁), aminomethyl (C₁), 1-chloroethyl (C₂),     2-hydroxyethyl (C₂), 1,2-difluoroethyl (C₂), 3-carboxypropyl (C₃),     and the like. -   2) C₂-C₂₀ linear or branched alkenyl, non-limiting examples of which     include, ethenyl (C₂), 3-propenyl (C₃), 1-propenyl (also     2-methylethenyl) (C₃), isopropenyl (also 2-methylethen-2-yl) (C₃),     buten-4-yl (C₄), and the like; substituted C₂-C₂₀ linear or branched     alkenyl, non-limiting examples of which include, 2-chloroethenyl     (also 2-chlorovinyl) (C₂), 4-hydroxybuten-1-yl (C₄),     7-hydroxy-7-methyloct-4-en-2-yl (C₉),     7-hydroxy-7-methyloct-3,5-dien-2-yl (C₉), and the like. -   3) C₂-C₂₀ linear or branched alkynyl, non-limiting examples of which     include, ethynyl (C₂), prop-2-ynyl (also propargyl) (C₃),     propyn-1-yl (C₃), and 2-methyl-hex-4-yn-1-yl (C₇); substituted     C₂-C₂₀ linear or branched alkynyl, non-limiting examples of which     include, 5-hydroxy-5-methylhex-3-ynyl (C₇),     6-hydroxy-6-methylhept-3-yn-2-yl (C₈), 5-hydroxy-5-ethylhept-3-ynyl     (C₉), and the like.

B. Substituted and Unsubstituted C₁-C₂₀ Cyclic Hydrocarbyl:

For the purposes of the present invention the term “substituted and unsubstituted C₁-C₂₀ cyclic hydrocarbyl” encompasses 5 categories of units:

-   1) The term “carbocyclic” is defined herein as “encompassing rings     comprising from 3 to 20 carbon atoms, wherein the atoms which     comprise said rings are limited to carbon atoms, and further each     ring can be independently substituted with one or more moieties     capable of replacing one or more hydrogen atoms.” The following are     non-limiting examples of “substituted and unsubstituted C₃-C₂₀     carbocyclic rings” which encompass the following categories of     units:     -   i) carbocyclic rings having a single substituted or         unsubstituted hydrocarbon ring, non-limiting examples of which         include, cyclopropyl (C₃), 2-methyl-cyclopropyl (C₃),         cyclopropenyl (C₃), cyclobutyl (C₄), 2,3-dihydroxycyclobutyl         (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),         cyclopentadienyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆),         cycloheptyl (C₇), cyclooctanyl (C₈), decalinyl (C₁₀),         2,5-dimethylcyclopentyl (C₅), 3,5-dichlorocyclohexyl (C₆),         4-hydroxycyclohexyl (C₆), and 3,3,5-trimethylcyclohex-1-yl (C₆).     -   ii) carbocyclic rings having two or more substituted or         unsubstituted fused hydrocarbon rings, non-limiting examples of         which include, octahydropentalenyl (C₈), octahydro-1H-indenyl         (C₉), 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl (C₉),         decahydroazulenyl (C₁₀); bicyclo[6.2.0]decanyl (C₁₀),         decahydronaphthalenyl (C₁₀), and dodecahydro-1H-fluorenyl (C₁₃).     -   iii) carbocyclic rings which are substituted or unsubstituted         bicyclic hydrocarbon rings, non-limiting examples of which         include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl,         bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl,         bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl. -   2) The term “aryl” is defined herein as “units encompassing at least     one phenyl or naphthyl ring and wherein there are no heteroaryl or     heterocyclic rings fused to the phenyl or naphthyl ring and further     each ring can be independently substituted with one or more moieties     capable of replacing one or more hydrogen atoms.” The following are     non-limiting examples of “substituted and unsubstituted C₆-C₁₄ aryl     rings” which encompass the following categories of units:     -   i) C₆ or C₁₀ substituted or unsubstituted aryl rings; phenyl and         naphthyl rings whether substituted or unsubstituted,         non-limiting examples of which include, phenyl (C₆),         naphthylen-1-yl (C₁₀), naphthylen-2-yl (C₁₀), 4-fluorophenyl         (C₆), 2-hydroxyphenyl (C₆), 3-methylphenyl (C₆),         2-amino-4-fluorophenyl (C₆), 2-(N,N-diethylamino)phenyl (C₆),         2-cyanophenyl (C₆), 2,6-di-tert-butylphenyl (C₆),         3-methoxyphenyl (C₆), 8-hydroxynaphthylen-2-yl (C₁₀),         4,5-dimethoxynaphthylen-1-yl (C₁₀), and 6-cyano-naphthylen-1-yl         (C₁₀).     -   ii) C₆ or C₁₀ aryl rings fused with 1 or 2 saturated rings         non-limiting examples of which include,         bicyclo[4.2.0]octa-1,3,5-trienyl (C₈), and indanyl (C₉). -   3) The terms “heterocyclic” and/or “heterocycle” are defined herein     as “units comprising one or more C₁-C₂₀ rings having from 3 to 20     atoms wherein at least one atom in at least one ring is a heteroatom     chosen from nitrogen (N), oxygen (O), or sulfur (S), or mixtures of     N, O, and S, and wherein further the ring which comprises the     heteroatom is also not an aromatic ring.” The following are     non-limiting examples of “substituted and unsubstituted C₁-C₂₀     heterocyclic rings” which encompass the following categories of     units:     -   i) heterocyclic units having a single ring containing one or         more heteroatoms, non-limiting examples of which include,         diazirinyl (C₁), aziridinyl (C₂), urazolyl (C₂), azetidinyl         (C₃), pyrazolidinyl (C₃), imidazolidinyl (C₃), oxazolidinyl         (C₃), isoxazolinyl (C₃), isoxazolyl (C₃), thiazolidinyl (C₃),         isothiazolyl (C₃), isothiazolinyl (C₃), oxathiazolidinonyl (C₃),         oxazolidinonyl (C₃), hydantoinyl (C₃), tetrahydrofuranyl (C₄),         pyrrolidinyl (C₄), 1-methylpyrrolidinyl (C₄), morpholinyl (C₄),         4-methylmorpholinyl (C₄), piperazinyl (C₄), 1-methylpiperazinyl         (C₄), 1-acetylpiperazinyl (C₄), 1-methanesulfonyl-piperazinyl         (C₄), piperidinyl (C₅), 1-methylpiperidinyl (C₅),         2,2,6,6-tetramethyl-piperidinyl (C₅), dihydropyranyl (C₅),         tetrahydropyranyl (C₅), piperidin-2-onyl (valerolactam) (C₅),         2,3,4,5-tetrahydro-1H-azepinyl (C₆), 2,3-dihydro-1H-indole (C₈),         and 1,2,3,4-tetrahydro-quinoline (C₉).     -   ii) heterocyclic units having 2 or more rings one of which is a         heterocyclic ring, non-limiting examples of which include         hexahydro-1H-pyrrolizinyl (C₇),         3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl (C₇),         8-azabicyclo[3.2.1]octyl (C₇),         3a,4,5,6,7,7a-hexahydro-1H-indolyl (C₈),         1,2,3,4-tetrahydroquinolinyl (C₉), and         decahydro-1H-cycloocta[b]pyrrolyl (C₁₀). -   4) The term “heteroaryl” is defined herein as “encompassing one or     more C₁-C₂₀ rings comprising from 5 to 20 atoms wherein at least one     atom in at least one ring is a heteroatom chosen from nitrogen (N),     oxygen (O), or sulfur (S), or mixtures of N, O, and S, and wherein     further at least one of the rings which comprises a heteroatom is an     aromatic ring.” The following are non-limiting examples of     “substituted and unsubstituted C₁-C₂₀ heterocyclic rings” which     encompass the following categories of units:     -   i) heteroaryl rings containing a single ring, non-limiting         examples of which include, 1,2,3,4-tetrazolyl (C₁),         [1,2,3]triazolyl (C₂), [1,2,4]triazolyl (C₂), triazinyl (C₃),         thiazolyl (C₃), 1H-imidazolyl (C₃), oxazolyl (C₃), furanyl (C₄),         thiopheneyl (C₄), pyrimidinyl (C₄), 2-phenylpyrimidinyl (C₄),         pyridinyl (C₅), 3-methylpyridinyl (C₅), and         4-dimethylaminopyridinyl (C₅)     -   ii) heteroaryl rings containing 2 or more fused rings one of         which is a heteroaryl ring, non-limiting examples of which         include: 7H-purinyl (C₅), 9H-purinyl (C₅), 6-amino-9H-purinyl         (C₅), 5H-pyrrolo[3,2-d]pyrimidinyl (C₆),         7H-pyrrolo[2,3-]pyrimidinyl (C₆), pyrido[2,3-]pyrimidinyl (C₇),         2-phenylbenzo[d]thiazolyl (C₇), 1H-indolyl (C₈),         4,5,6,7-tetrahydro-1-H-indolyl (C₈), quinoxalinyl (C₈),         5-methylquinoxalinyl (C₈), quinazolinyl (C₈), quinolinyl (C₉),         8-hydroxy-quinolinyl (C₉), and isoquinolinyl (C₉). -   5) C₁-C₆ tethered cyclic hydrocarbyl units (whether C₃-C₁₀     carbocyclic units, C₆ or C₁₀ aryl units, C₁-C₁₀ heterocyclic units,     or C₁-C₁₀ heteroaryl units) which connected to another moiety, unit,     or core of the molecule by way of a C₁-C₆ alkylene unit.     Non-limiting examples of tethered cyclic hydrocarbyl units include     benzyl C₁-(C₆) having the formula:

-   -   wherein R^(a) is optionally one or more independently chosen         substitutions for hydrogen. Further examples include other aryl         units, inter alia, (2-hydroxyphenyl)hexyl C₆—(C₆);         naphthalen-2-ylmethyl C₁-(C₁₀), 4-fluorobenzyl C₁-(C₆),         2-(3-hydroxy-phenyl)ethyl C₂—(C₆), as well as substituted and         unsubstituted C₃-C₁₀ alkylenecarbocyclic units, for example,         cyclopropylmethyl C₁-(C₃), cyclopentylethyl C₂—(C₅),         cyclohexylmethyl C₁-(C₆). Included within this category are         substituted and unsubstituted C₁-C₁₀ alkylene-heteroaryl units,         for example a 2-picolyl C₁-(C₆) unit having the formula:

-   -   wherein R^(a) is the same as defined above. In addition, C₁-C₁₂         tethered cyclic hydrocarbyl units include C₁-C₁₀         alkyleneheterocyclic units and alkylene-heteroaryl units,         non-limiting examples of which include, aziridinylmethyl C₁-(C₂)         and oxazol-2-ylmethyl C₁-(C₃).

For the purpose of the present invention fused ring units, as well as spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring. For example, 1,2,3,4-tetrahydroquinoline having the formula:

is, for the purposes of the present invention, considered a heterocyclic unit. 6,7-Dihydro-5H-cyclopentapyrimidine having the formula:

is, for the purposes of the present invention, considered a heteroaryl unit. When a fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned. For example, 1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula:

is, for the purposes of the present invention, considered a heteroaryl unit.

The term “substituted” is used throughout the specification. The term “substituted” is defined herein as “a hydrocarbyl moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several substituents as defined herein below.” The units, when substituting for hydrogen atoms are capable of replacing one hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety, or unit. For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. Three hydrogen replacements includes cyano, and the like. The term substituted is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain; can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as “substituted” any number of the hydrogen atoms may be replaced. For example, 4-hydroxyphenyl is a “substituted aromatic carbocyclic ring”, (N,N-dimethyl-5-amino)octanyl is a “substituted C₈ alkyl unit, 3-guanidinopropyl is a “substituted C₃ alkyl unit,” and 2-carboxypyridinyl is a “substituted heteroaryl unit.”

The following are non-limiting examples of categories and examples herewith of units which can suitably substitute for hydrogen atoms on a cyclic or acyclic hydrocarbyl unit, described herein below as R⁵ units, wherein in the non-limiting examples provided herein below, R¹² is hydrogen, C₁-C₁₀ linear or branched alkyl, C₂-C₁₀ linear or branched alkenyl, C₂-C₁₀ linear or branched alkynyl, and C₆ or C₁₀ aryl.

R⁵ units according to the present invention may include the following substitutions either comprising R⁵ itself or when R⁵ comprises an R⁶ unit which is bonded to the core phenyl unit by a linking unit:

-   -   i) —NHCOR¹²; for example, —NHCOCH₃, —NHCOCH₂CH₃, —NHCOC₆H₅;     -   ii) —COR¹²; for example, —COCH₃, —COCH₂CH₃, —COCH₂CH₂CH₃;     -   iii) —CO₂R¹²; for example, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃;     -   iv) —OCOR¹²; for example, —OCOCH₃, —OCOCH₂CH₃, —OCOCH₂CH₂CH₃;     -   v) —C(═NH)NH₂;     -   vi) —NHC(═NH)NH₂;     -   vii) —N(R¹²)₂; for example, —NH₂, —NHCH₃, —N(CH₃)₂, —NH(CH₂CH₃);     -   viii) —NHC₆H₅;     -   ix) C₁-C₄ linear, branched, or cyclic alkyl; for example,         methyl, ethyl;     -   x) —CON(R¹²)₂; for example, —CONH₂, —CONHCH₃, —CON(CH₃)₂;     -   xi) —CONHNH₂;     -   xii) —NHCN;     -   xiii) —CN;     -   xiv) halogen: —F, —Cl, —Br, and —I;     -   xv) —NHN(R¹²)₂; for example, —NHNH₂, —NHNHCH₃, —NHN(CH₃)₂;     -   xvi) —OR¹²; for example, —OH, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃;     -   xvii) —NO₂;     -   xviii) —CH_(m)X_(3-m); wherein X is halogen, m is from 0 to 2;         for example, —CH₂F, —CHF₂, —CF₃, —CCl₃, or —CBr₃; and     -   xix) —SO₂N(R¹²)₂; for example, —SO₂NH₂; —SO₂NHCH₃; —SO₂NHC₆H₅.

For the purposes of the present invention the terms “compound” and “analog” stand equally well for the novel compositions of matter described herein, including all enantiomeric forms, diastereomeric forms, salts, and the like, and the terms “compound” and “analog” are used interchangeably throughout the present specification.

The compounds of the present invention are 2-arylamino-4-(heterocyclicalkylene)-aminopyrimidines having the core scaffold:

which includes a core pyrimidine ring and a core phenyl ring wherein R⁵ represents one or more (from 1 to 5) optionally present, and independently selected, substitutes for hydrogen as outlined herein above and described in the categories, aspects, iterations, examples, and tables herein below. As it relates to particularly pointing out the subject matter of the present invention, the unit R¹ which contains the core phenyl ring, may be depicted throughout the specification and claims equally well by the following general formulae:

wherein R, R¹, R⁵, R⁶, L, L¹ and y are further described herein below.

R units are substituted or unsubstituted heterocyclic units containing from 3 to 7 atoms.

The first category of R units relates to heterocyclic units wherein the linking group L is bonded to a nitrogen atom, said units having the formula:

wherein R² and R³ are taken together to form a heterocycle having from 3 to 7 atoms optionally substituted with one or more substituents.

The first aspect of category one of R units relates to C₃, C₄ and C₅ unsubstituted heterocycles. Non-limiting examples of this aspect includes units chosen from pyrrolidin-1-yl, pyrrolin-1-yl, imidazolidin-1-yl, imidazolin-1-yl, pyrazolidin-1-yl, pyrazolin-1-yl, piperidin-1-yl, piperazin-1-yl, and morpholin-4-yl.

The second aspect of category one of R units relates to C₃, C₄ and C₅ substituted heterocycles. Non-limiting examples of this aspect includes units chosen from 5,5-di-methyl-imidazolin-1-yl, 4-methylpiperazin-1-yl, 4-acetylpiperazin-1-yl, and 4-methane-sulfonyl-piperazin-1-yl.

The second category of R units relates to heterocyclic units wherein the linking group L is bonded to a carbon atom, the first aspect of said units having the formula:

wherein R² and R³ are taken together to form a heterocycle having from 3 to 7 atoms optionally substituted with one or more substituents; R¹⁰ is methyl, ethyl, 1-propyl, 2-propyl, or phenyl.

One iteration of the first aspect of category two of R units relates to C₃, C₄ and C₅ substituted or unsubstituted heterocycles non-limiting examples of which include units chosen from pyrrolidin-2-yl, N-methyl-pyrrolidin-2-yl, N-methyl-pyrrolidin-2-one-5-yl, pyrrolin-2-yl, imidazolidin-2-yl, imidazolin-2-yl, pyrazolidin-2-yl, pyrazolin-2-yl, piperidin-2-yl, N-methylpiperidin-2-yl, morpholin-3-yl, and N-methylmorpholin-3-yl.

A further iteration of the first aspect of category two of R units relates to C₃, C₄ and C₅ substituted or unsubstituted heterocycles having a chiral center in the R units and wherein a particular enantiomer is selected, for example, one of the two enantiomeric R units having the formula:

The second aspect of the second category of R units relates to heterocyclic units wherein the linking group L is bonded to a carbon atom, said units having the formula:

wherein R² and R³ are taken together to form a heterocycle having from 3 to 7 atoms optionally substituted with one or more substituents; R¹⁰ is methyl, ethyl, 1-propyl, 2-propyl, or phenyl. Non-limiting examples of this aspect includes pyrrolidin-3-yl, N-methyl-pyrrolidin-3-yl, piperidin-3-yl, N-methylpiperidin-3-yl, morpholin-2-yl, and N-methylmorpholin-2-yl.

The third aspect of the second category of R units relates to heterocyclic units wherein the linking group L is bonded to a carbon atom, said units having the formula:

wherein R² and R³ are taken together to form a heterocycle having from 3 to 7 atoms optionally substituted with one or more substituents; R¹⁰ is methyl, ethyl, 1-propyl, 2-propyl, or phenyl. Non-limiting examples of this aspect include piperidin-4-yl, N-methylpiperidin-4-yl, and 2,2,6,6-tetramethyl-piperidin-4-yl.

R¹ is substituted or unsubstituted phenyl having the formula:

R⁵ is hydrogen or one or more independently chosen substitutes for hydrogen, R⁵ has the formula:

-(L¹)_(y)-R⁶

the index y has the value 0 when L¹ is absent, and the value 1 when L¹ is present; R⁶ is a unit chosen from:

-   -   i) hydrogen;     -   ii) halogen;     -   iii) nitro;     -   iv) hydroxy;     -   v) amino or mono- or di-substituted (C₁-C₄ linear or branched         alkyl)amino;     -   vi) substituted or unsubstituted C₁-C₄ linear or branched alkyl;     -   vii) substituted or unsubstituted C₁-C₄ linear or branched         alkoxy;     -   viii) substituted or unsubstituted phenyl;     -   ix) substituted or unsubstituted C₂-C₅ heterocyclic;     -   x) substituted or unsubstituted C₃-C₉ heteroaryl;     -   xi) cyano; or     -   xii) CH_(m)X_(3-m) wherein X is halogen and m is from 0 to 2.

The first category of R¹ relates to substituted phenyl units wherein L¹ is absent (the index y is equal to 0) and R⁵ comprises one or more substitutes for hydrogen each of which is independently chosen from:

-   -   ii) halogen; —F, —Cl, —Br, and —I;     -   iii) nitro; —NO₂;     -   iv) hydroxy; —OH;     -   v) amino or mono- or di-substituted (C₁-C₄ linear or branched         alkyl)amino; inter alia, —NH₂, —NH(CH₃), and —N(CH₃)₂;     -   vi) substituted or unsubstituted C₁-C₄ linear or branched alkyl;     -   vii) substituted or unsubstituted C₁-C₄ linear or branched         alkoxy.

The first aspect of Category one of R¹ relates to units which are substituted by one or more units from groups (ii)-(vii). Non-limiting examples of this aspect include 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 3-trifluoromethylphenyl, 3-trifluoromethyl-4-chlorophenyl, 3-methoxyphenyl, 3-methylphenyl, 3-ethylphenyl, and 3-isopropylphenyl.

The second aspect of Category one of R¹ relates to units which are substituted by one or more halogen atom, for example, —F, —Cl, —Br, and —I. Non-limiting examples of this aspect include 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, and 2,4,6-trichlorophenyl.

The third aspect of Category one of R¹ relates to units which are substituted by one or more C₁-C₄ linear or branched alkyl, for example, methyl (C₁), ethyl (C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), and tert-butyl (C₄). Non-limiting examples of this aspect include 2-methylphenyl, 4-methylphenyl, 2,3-dimethyl-phenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethyl-phenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethyl-phenyl, 2,3,6-trimethylphenyl, 2,4,5-tri-methylphenyl, 2,4,6-trimethylphenyl, 2-ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethyl-phenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, and 2,4,6-triethyl-phenyl.

The fourth aspect of Category one of R¹ relates to units which are substituted by one or more C₁-C₄ linear or branched alkoxy, for example, methoxy (C₁), ethoxy (C₂), n-propoxy (C₃), iso-propoxy (C₃), n-butoxy (C₄), sec-butoxy (C₄), iso-butoxy (C₄), and tert-butoxy (C₄). Non-limiting examples of this aspect include 2-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6-trimethoxy-phenyl, 2,4,5-trimethoxyphenyl, and 2,4,6-trimethoxyphenyl.

The fifth aspect of Category one of R¹ relates to units which are substituted by one or more hydroxy units, non-limiting examples of this aspect include 2-hydroxy-phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4-dihydroxy-phenyl, 2,3,4-trihydroxyphenyl, 2,3,5-trihydroxy-phenyl, 2,3,6-trihydroxyphenyl, 2,4,5-trihydroxyphenyl, and 2,4,6-trihydroxyphenyl.

Other aspects of Category one of R¹ include combinations of R⁵ substituents which comprise substitute classes (ii)-(vii) not specifically exemplified herein.

The second category of R¹ relates to substituted core phenyl units wherein the index y is equal to 0 or 1 and R⁵ comprises one or more substitutes for hydrogen each of which is independently chosen from units which comprise:

-   -   viii) substituted or unsubstituted phenyl; or     -   ix) substituted or unsubstituted C₃-C₉ heteroaryl units.

Substituted or unsubstituted phenyl units are present in the second category of R¹ when linked to the core phenyl units by way of a linking unit L¹.

The core C₃-C₉ heteroaryl rings of the second category of R¹ encompass the following non-limiting examples of substituted and unsubstituted rings: triazinyl (C₃), thiazoyl (C₃), 1H-imidazoyl (C₃), furanyl (C₄), thiophenyl (C₄), pyrimidinyl (C₄), 2-phenylpyrimidinyl (C₄), pyridinyl (C₅), 3-methylpyridinyl (C₅), 4-dimethylaminopyridinyl (C₅), 7H-purinyl (C₅), 9H-purinyl (C₅), 6-amino-9H-purinyl (C₅), 5H-pyrrolo[3,2-d]pyrimidinyl (C₆), 7H-pyrrolo[2,3-d]pyrimidinyl (C₆), pyrido[2,3-d]pyrimidinyl (C₇), 2-phenylbenzo[d]thiazolyl (C₇), 4,5,6,7-tetrahydro-1-H-indolyl (C₉), quinoxalinyl (C₈), 5-methylquinoxalinyl (C₈), quinazolinyl (C₈), 6,7-dihydro-5H-[1]pyridine (C₈), quinolinyl (C₉), 8-hydroxy-quinolinyl (C₉), and isoquinolinyl (C₉).

The first aspect of the second category of R¹ relates to units wherein the linking unit L¹ is absent (the index y is equal to 0), non-limiting examples of which include units chosen from: 2-(pyrimidin-2-yl)phenyl, 2-(pyrimidin-3-yl)phenyl, 2-(pyrimidin-4-yl)phenyl, 3-(pyrimidin-2-yl)phenyl, 3-(pyrimidin-3-yl)phenyl, 3-(pyrimidin-4-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-3-yl)phenyl, 4-(pyrimidin-4-yl)phenyl, 2-(pyridin-2-yl)phenyl, 2-(pyridin-3-yl)phenyl, 2-(pyridin-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 4-(pyridin-2-yl)phenyl, 4-(pyridin-3-yl)phenyl, and 4-(pyridin-4-yl)phenyl.

The second aspect of the second category of R¹ relates to units wherein L¹ is a unit having the formula:

—[CH₂]_(j)—

wherein the index j is equal to 1 or 2, non-limiting examples of which include units chosen from: 2-[(pyrimidin-2-yl)phenyl]methyl, 2-[(pyrimidin-3-yl)phenyl]methyl, 2-[(pyrimidin-4-yl)phenyl]methyl, 3-[(pyrimidin-2-yl)phenyl]methyl, 3-[(pyrimidin-3-yl)phenyl]methyl, 3-[(pyrimidin-4-yl)phenyl]methyl, 4-[(pyrimidin-2-yl)phenyl]methyl, 4-[(pyrimidin-3-yl)phenyl]methyl, 4-[(pyrimidin-4-yl)phenyl]methyl, 2-[(pyridin-2-yl)phenyl]methyl, 2-[(pyridin-3-yl)phenyl]methyl, 2-[(pyridin-4-yl)phenyl]methyl, 3-[(pyridin-2-yl)phenyl]methyl, 3-[(pyridin-3-yl)phenyl]methyl, 3-[(pyridin-4-yl)phenyl]-methyl, 4-[(pyridin-2-yl)phenyl]methyl, 4-[(pyridin-3-yl)phenyl]methyl, and 4-[(pyridin-4-yl)phenyl]methyl.

The third aspect of the second category of R¹ relates to units wherein L¹ is a unit having the formula:

—O[CH₂]_(k)

wherein the index k is equal to 1 or 2, non-limiting examples of which include R⁵ units chosen from: 2-(pyrimidin-2-yl)phenyl, 2-(pyrimidin-3-yl)phenyl, 2-(pyrimidin-4-yl)phenyl, 3-(pyrimidin-2-yl)phenyl, 3-(pyrimidin-3-yl)phenyl, 3-(pyrimidin-4-yl)phenyl, 4-(pyrimidin-2-yl)phenyl, 4-(pyrimidin-3-yl)phenyl, 4-(pyrimidin-4-yl)phenyl, 2-(pyridin-2-yl)phenyl, 2-(pyridin-3-yl)phenyl, 2-(pyridin-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 4-(pyridin-2-yl)phenyl, 4-(pyridin-3-yl)phenyl, and 4-(pyridin-4-yl)phenyl.

The fourth aspect of the second category of R¹ relates to units wherein L¹ is a unit having the formula:

—SO₂NH—

and R⁵ is a unit chosen from:

-   -   i) hydrogen;     -   ii) C₁-C₄ linear or branched alkyl;     -   iii) substituted or unsubstituted phenyl; and     -   iv) substituted or unsubstituted heteroaryl.

The first iteration of the fourth aspect of category two of R¹ units encompasses R⁵ units which are chosen from:

-   -   i) hydrogen; or     -   ii) C₁-C₄ linear or branched alkyl.

Non-limiting examples of R¹ units encompassed within this iteration include: benzene-sulfonamide, N-methyl-benzenesulfonamide, N-ethyl-benzenesulfon-amide, N-(n-propyl)-benzenesulfonamide, N-(iso-propyl)-benzenesulfonamide, N-(n-butyl)-benzenesulfonamide, N-(sec-butyl)-benzenesulfonamide, N-(iso-butyl)-benzenesulfonamide, and N-(tert-butyl)-benzenesulfonamide.

The second iteration of the fourth aspect of category two of R¹ units encompasses R⁵ units which are chosen from:

-   -   iii) substituted or unsubstituted phenyl; or     -   iv) substituted or unsubstituted heteroaryl.

Non-limiting examples of R¹ units encompassed within this iteration include: N-phenyl-benzene-sulfonamide, N-(pyrimidin-2-yl)-benzenesulfonamide, N-(pyrimidin-4-yl)-benzenesulfonamide, N-(pyrimidin-5-yl)-benzenesulfonamide, N-(pyridin-2-yl)-benzenesulfonamide, N-(pyridin-3-yl)-benzenesulfonamide, and N-(pyridin-4-yl)-benzenesulfonamide.

The fifth aspect of the second category of R¹ relates to units wherein L¹ is a unit having the formula:

—[C(R^(7a)R^(7b))]_(j)NR⁹C(O)[C(R^(8a)R^(8b))]_(k)—; or

—[C(R^(7a)R^(7b))]_(j)C(O)NR⁹[C(R^(8a)R^(8b))]_(k)—

wherein R^(7a), R^(7b), R^(8a), R^(8b), and R⁹ are each independently hydrogen, methyl, or ethyl; the indices j and k are each independently from 0 to 3.

The first iteration of the fifth aspect of the second category of R¹ units relates to R¹ units wherein R⁶ units are linked to the phenyl ring by way of a L¹ unit chosen from units having the formula:

-   -   i) —NH(CO)—;     -   ii) —NH(CO)CH₂—; and     -   iii) —C(O)NH—;         and R⁶ comprises a unit chosen from:     -   viii) substituted or unsubstituted phenyl; or     -   x) substituted or unsubstituted C₃-C₉ heteroaryl.

Non-limiting examples of the first iteration of the fifth aspect of the second category of R¹ units includes substituted or unsubstituted phenyl units linked with amide bond linking units having the formula —C(O)NH— or —NH(CO)—. The following are examples of R⁵ units which are amide bond-linked substituted or unsubstituted phenyl units substituted at the 3-position of the core phenyl ring:

wherein R¹¹ comprises one or more of the R¹² substitutions for hydrogen as defined and exemplified herein above.

The third category of R¹ relates to substituted phenyl units wherein L¹ is absent (the index y is equal to 0) and R⁵ comprises one or more substitutes for hydrogen each of which is independently chosen from units which comprise:

-   -   viii) substituted or unsubstituted C₂-C₅ heterocyclic units.

The core C₂-C₅ heterocyclic rings of the third category of R¹ encompass the following unsubstituted rings: aziridinyl (C₂), [1,2,3]triazolyl (C₂), [1,2,4]triazolyl (C₂), urazolyl (C₂), oxazolyl (C₃), azetidinyl (C₃), pyrazolidinyl (C₃), imidazolidinyl (C₃), oxazolidinyl (C₃), isoxazolinyl (C₃), oxazolyl (C₃) isoxazolyl (C₃), thiazolidinyl (C₃), thiazolyl (C₃), imidazolidinonyl (C₃), isothiazolyl (C₃), isothiazolinyl (C₃), oxathiazolidinonyl (C₃), oxazolidinonyl (C₃), hydantoinyl (C₃), tetrahydrofuranyl (C₄), pyrrolidinyl (C₄), tetrahydrothiophenyl (C₄), morpholinyl (C₄), piperazinyl (C₄), piperidinyl (C₄), dihydropyranyl (C₅), tetrahydropyranyl (C₅), and piperidin-2-onyl (valerolactam) (C₅). However, the C₂-C₅ heterocyclic rings described herein can be substituted with one or more units chosen from:

-   -   i) C₁-C₄ linear or branched alkyl, for example, methyl (C₁),         ethyl (C₂), n-propyl (C₃), iso-propyl (C₃), n-butyl (C₄),         sec-butyl (C₄), iso-butyl (C₄), and tert-butyl (C₄); or     -   ii) amino —NH₂, or mono- or di-[C₁-C₄ linear or branched         alkyl]substituted amino, for example, —NH₂; —NHCH₃; —N(CH₃)₂;         —NH(CH₂CH₃); —N(CH₂CH₃)₂; —N(CH₃)(CH₂CH₃); —NH(CH₂CH₂CH₃);         —N[CH(CH₃)₂]₂; —N(CH₂CH₂CH₃)₂; —NH[CH(CH₃)₂];         —N(CH₂CH₂CH₃)[CH(CH₃)₂]; —N(CH₃)(CH₂CH₂CH₃);         —N(CH₂CH₃)(CH₂CH₂CH₃); —N[C(CH₃)₃]₂; —N(CH₃)[CH(CH₃)₂];         —N(CH₂CH₃)[CH(CH₃)₂]₂; —NH[C(CH₃)₃]; —NH(CH₂CH₂CH₂CH₃);         —N(CH₂CH₂CH₂CH₃)₂; —NH[CH₂CH(CH₃)₂]; —N[CH₂CH(CH₃)₂]₂;         —NH[CH(CH₃)CH₂CH₃]; —N[CH(CH₃)CH₂CH₃]₂;         —N(CH₂CH₂CH₂CH₃)[CH₂CH(CH₃)₂]; —N(CH₂CH₂CH₂CH₃)[C(CH₃)₃]; and         —N(CH₂CH₂CH₂CH₃) [CH(CH₃)CH₂CH₃]     -   L is a linking unit having the formula:

—[C(R^(4a)R^(4b))]_(n)—

wherein each R^(4a) and R^(4b) unit is independently chosen from:

-   -   i) hydrogen; or     -   ii) C₁-C₄ linear, branched, or cyclic alkyl; for example, methyl         (C₁), ethyl (C₂), n-propyl(C₃), iso-propyl (C₃), cyclopropyl         (C₃), n-butyl (C₄), iso-butyl (C₄), sec-butyl (C₄), and         tert-butyl (C₄);         the index n is from 1 to 4. The index n indicates the number of         units which comprise L linking units, for example, a linking         unit having the formula —CH₂— (methylene) would have an index n         equal to 1. A linking unit having the formula —CH₂CH₂—         (ethylene) or the unit having the formula —CH(CH₃)CH₂—         (1-methylethylene) each have an index n equal to 2.

The first category of L units relates to unsubstituted alkylene units chosen from:

-   -   i) —CH₂—, methylene;     -   ii) —CH₂CH₂—, ethylene;     -   iii) —CH₂CH₂CH₂—, propylene; and     -   iv) —CH₂CH₂CH₂CH₂—, butylene.

The first aspect of the first category of L units encompasses linking groups which are —CH₂CH₂CH₂—, propylene; as exemplified in the generic formula:

The second aspect of the first category of L units encompasses linking groups which are —CH₂CH₂—, ethylene.

The second category of L units relates to alkyl substituted alkylene units chosen from:

-   -   i) —CH(CH₃)CH₂—, 1-methylethylene;     -   ii) —CH₂CH(CH₃)—, 2-methylethylene;     -   iii) —CH(CH₃)CH₂CH₂—, 1-methylpropylene;     -   iv) —CH₂CH(CH₃)CH₂—, 2-methylpropylene; and     -   v) —CH₂C(CH₃)₂CH₂—, 2,2-dimethylpropylene.

The first aspect of the second category of L units encompasses linking groups which are —CH(CH₃)CH₂CH₂—, 1-methylpropylene; as exemplified in the generic formula:

wherein the above formula encompasses both the R and the S enantiomers of the linking unit.

L¹ is a linking unit which when present provides R⁵ units with the formula:

-(L¹)_(y)-R⁶

wherein y is equal to 1 when L¹ is present.

-   -   L¹ is a linking unit chosen from:     -   i) —[C(R^(7a)R^(7b))]_(j)—;     -   ii) —[C(R^(7a)R^(7b))]_(j)O[C(R^(8a)R^(8b))]_(k)—;     -   iii) —[C(R^(7a)R^(7b))]_(j)NR⁹SO₂[C(R^(8a)R^(8b))]_(k)—;     -   iv) —[C(R^(7a)R^(7b))]_(j)SO₂NR⁹[C(R^(8a)R^(8b))]_(k)—;     -   v) —[C(R^(7a)R^(7b))]_(j)NR⁹C(O)[C(R^(8a)R^(8b))]_(k)—;     -   vi) —[C(R^(7a)R^(7b))]_(j)C(O)NR⁹[C(R^(8a)R^(8b))]_(k); or     -   vii) —[C(R^(7a)R^(7b))]_(j)SO₂NR⁹[C(R^(7a)R^(7b))]_(k)—;         R^(7a), R^(7b), R^(8a), R^(8b), and R⁹ are each independently         hydrogen, methyl, or ethyl; the indices j and k are each         independently from 0 to 3; the index y is 0 or 1.

The various categories, aspects, iterations, and examples of L¹ can be found in the definitions of R¹ and in the examples and tables described and listed herein below.

Synthesis Procedure

The compounds of the present invention can be prepared by the following general procedure, the formulator adjusting the reaction conditions as is necessary and which one skilled in the art will be able to accomplish without undo experimentation.

Step 1: Preparation of intermediate 2-(methylthio)pyrimidine-4(3H)-one. This compound can be used in the preparation of each analog encompassed by the present invention. The general procedure follows.

To a solution of sodium hydroxide (8 g, 200 mmol) in H₂O (75 mL) at room temperature is added thiouridine (14.2 g, 100 mmol). The resulting mixture is stirred at room temperature for 20 minutes. Methyl iodide (6.86 mL, 110 mmol) in THF (10 mL) is added dropwise slowly and the mixture is stirred at room temperature for 18 hours. A white solid forms upon acidifying the mixture to pH 5 with glacial acetic acid. At this point the mixture is cooled in an ice bath and allowed to stand for approximately 2 hours after which the final product separates as a white solid and can be collected by filtration. First crop of crystals typically yields the desired product in an excess of 60% yield. ¹H NMR (DMSO-d₆, 300 MHz): δ 2.45 (s, 3H), 6.07 (d, J=6.6 Hz, 1H), 7.85 (d, J=6.6 Hz, 1H).

Step 2: Formation of 2-anilino Intermediate.

2-(Substituted or unsubstituted phenylamino)pyrimidin-4(3H)-one: To a 2-(methyl-thio)pyrimidine-4(3H)-one (14.2 g, 100 mmol) in diglyme (60 mL) is added the substituted or unsubstituted aniline of choice (200 mmol). The resulting mixture is heated to reflux and stirred for approximately 18 hours. The product which typically forms as a solid upon cooling the mixture to room temperature, is washed with solvent (pentane, hexane, or isopentane). However, solvent can be added to the reaction mixture to induce crystallization if necessary.

Step 3. Formation of 4-chloro-2-anilino Intermediate.

2-(Substituted or unsubstituted phenylamino)-4-chloro-pyrimidine: To a 2-(Substituted or unsubstituted phenylamino)pyrimidin-4(3H)-one (5.02 g, 22.6 mmol) and N,N-dimethyl-aniline (450 mL) is added of phosphorus oxychloride (450 mL). The resulting mixture is heated to reflux for 15 minutes, cooled to room temperature and concentrated in vacuo. The residue is neutralized to pH 7 with 1M NaOH (aqueous). The organic layer is extracted with EtOAc (3×250 mL). The combined organic layers are dried (MgSO₄) and concentrated in vacuo. The residue can be conveniently purified over silica (5% EtOAc in hexanes) to afford the desired compound.

Alternatively, the 4-chloro-2-anilino intermediate can be synthesized the following way:

2-(Substituted or unsubstituted phenylamino)-4-chloro-pyrimidine: To a 2-(substituted or unsubstituted phenylamino)pyrimidin-4(3H)-one (3.00 g, 13.5 mmol) in toluene (30 mL) is added N,N-dimethyl-aniline (3.57 mL, 28.4 mmol) and phosphorus oxychloride (1.24 mL, 13.5 mmol). The resulting mixture is heated to reflux for 15 minutes, cooled to room temperature and neutralized to pH 7 with 1M NaOH (aqueous). The organic layer is extracted with EtOAc (3×250 mL). The combined organic layers are dried (MgSO₄) and concentrated in vacuo. The residue can be conveniently purified over silica (5% EtOAc in hexanes) to afford the desired compound.

Step 4. Formation of Final Compounds (Analogs) of the Present Invention.

To the 2-(Substituted or unsubstituted phenylamino)pyrimidin-4(3H)-one formed in Step (2) (100 mmol) in THF (500 mL) is added diisopropylethylamine (200 mmol) followed by the desired diamine (200 mmol). The resulting mixture is heated to reflux for approximately 18 hours. The reaction is cooled to room temperature and concentrated in vacuo. The residue which forms is diluted with water and extracted with solvent. The combined organic layers are dried (MgSO₄) and concentrated in vacuo. This residue can be crystallized or purified over silica to afford the final compound.

Schemes I-IV herein below provide illustrative examples of the preparation of compounds encompassed by the various categories of the present invention.

The analogs (compounds) of the present invention are arranged into several categories to assist the formulator in applying a rational synthetic strategy for the preparation of analogs which are not expressly exampled herein. The arrangement into categories does not imply increased or decreased efficacy for any of the compositions of matter described herein.

Analog Categories

The compounds which comprise Category I of the present invention are 2,4-di-aminopyrimidines having the formula:

wherein linking group L is a propylene (—CH₂CH₂CH₂—) unit and R units are heterocyclic units attached to the core scaffold by way of a ring nitrogen atom. The first aspect of Category I encompasses R¹ units which are phenyl units substituted by one or more R⁵ units chosen from:

-   -   i) halogen; —F, —Cl, —Br, and —I;     -   ii) nitro; —NO₂;     -   iii) hydroxy; —OH;     -   iv) amino or mono- or di-(substituted C₁-C₄ alkyl)amino; inter         alia, —NH₂, —NH(CH₃), and —N(CH₃)₂,     -   v) substituted or unsubstituted C₁-C₄ linear or branched alkyl;     -   vi) substituted or unsubstituted C₁-C₄ linear or branched         alkoxy;         which are further exemplified herein below in Table I.

TABLE I No R R¹ 1 pyrrolidin-1-yl 3-chlorophenyl 2 pyrrolin-1-yl 3-chlorophenyl 3 imidazolidin-1-yl 3-chlorophenyl 4 imidazolin-1-yl 3-chlorophenyl 5 pyrazolidin-1-yl 3-chlorophenyl 6 pyrazolin-1-yl 3-chlorophenyl 7 piperidin-1-yl 3-chlorophenyl 8 piperazin-1-yl 3-chlorophenyl 9 4-methylpiperazin-1- 3-chlorophenyl yl 10 morpholin-4-yl 3-chlorophenyl 11 pyrrolidin-1-yl 4-chlorophenyl 12 pyrrolin-1-yl 4-chlorophenyl 13 imidazolidin-1-yl 4-chlorophenyl 14 imidazolin-1-yl 4-chlorophenyl 15 pyrazolidin-1-yl 4-chlorophenyl 16 pyrazolin-1-yl 4-chlorophenyl 17 piperidin-1-yl 4-chlorophenyl 18 piperazin-1-yl 4-chlorophenyl 19 4-methylpiperazin-1- 4-chlorophenyl yl 20 morpholin-4-yl 4-chlorophenyl 21 pyrrolidin-1-yl 3,4-dichlorophenyl 22 pyrrolin-1-yl 3,4-dichlorophenyl 23 imidazolidin-1-yl 3,4-dichlorophenyl 24 imidazolin-1-yl 3,4-dichlorophenyl 25 pyrazolidin-1-yl 3,4-dichlorophenyl 26 pyrazolin-1-yl 3,4-dichlorophenyl 27 piperidin-1-yl 3,4-dichlorophenyl 28 piperazin-1-yl 3,4-dichlorophenyl 29 4-methylpiperazin-1- 3,4-dichlorophenyl yl 30 morpholin-4-yl 3,4-dichlorophenyl 31 pyrrolidin-1-yl 3-chloro-4-methylphenyl 32 pyrrolin-1-yl 3-chloro-4-methylphenyl 33 imidazolidin-1-yl 3-chloro-4-methylphenyl 34 imidazolin-1-yl 3-chloro-4-methylphenyl 35 pyrazolidin-1-yl 3-chloro-4-methylphenyl 36 pyrazolin-1-yl 3-chloro-4-methylphenyl 37 piperidin-1-yl 3-chloro-4-methylphenyl 38 piperazin-1-yl 3-chloro-4-methylphenyl 39 4-methylpiperazin-1- 3-chloro-4-methylphenyl yl 40 morpholin-4-yl 3-chloro-4-methylphenyl 41 pyrrolidin-1-yl 3-chloro-4-fluorophenyl 42 pyrrolin-1-yl 3-chloro-4-fluorophenyl 43 imidazolidin-1-yl 3-chloro-4-fluorophenyl 44 imidazolin-1-yl 3-chloro-4-fluorophenyl 45 pyrazolidin-1-yl 3-chloro-4-fluorophenyl 46 pyrazolin-1-yl 3-chloro-4-fluorophenyl 47 piperidin-1-yl 3-chloro-4-fluorophenyl 48 piperazin-1-yl 3-chloro-4-fluorophenyl 49 4-methylpiperazin-1- 3-chloro-4-fluorophenyl yl 50 morpholin-4-yl 3-chloro-4-fluorophenyl 51 pyrrolidin-1-yl 3,4-difluorophenyl 52 pyrrolin-1-yl 3,4-difluorophenyl 53 imidazolidin-1-yl 3,4-difluorophenyl 54 imidazolin-1-yl 3,4-difluorophenyl 55 pyrazolidin-1-yl 3,4-difluorophenyl 56 pyrazolin-1-yl 3,4-difluorophenyl 57 piperidin-1-yl 3,4-difluorophenyl 58 piperazin-1-yl 3,4-difluorophenyl 59 4-methylpiperazin-1- 3,4-difluorophenyl yl 60 morpholin-4-yl 3,4-difluorophenyl 61 pyrrolidin-1-yl 3-CF₃-phenyl 62 pyrrolin-1-yl 3-CF₃-phenyl 63 imidazolidin-1-yl 3-CF₃-phenyl 64 imidazolin-1-yl 3-CF₃-phenyl 65 pyrazolidin-1-yl 3-CF₃-phenyl 66 pyrazolin-1-yl 3-CF₃-phenyl 67 piperidin-1-yl 3-CF₃-phenyl 68 piperazin-1-yl 3-CF₃-phenyl 69 4-methylpiperazin-1- 3-CF₃-phenyl yl 70 morpholin-4-yl 3-CF₃-phenyl 71 pyrrolidin-1-yl 3-CF₃-4-Cl-phenyl 72 pyrrolin-1-yl 3-CF₃-4-Cl-phenyl 73 imidazolidin-1-yl 3-CF₃-4-Cl-phenyl 74 imidazolin-1-yl 3-CF₃-4-Cl-phenyl 75 pyrazolidin-1-yl 3-CF₃-4-Cl-phenyl 76 pyrazolin-1-yl 3-CF₃-4-Cl-phenyl 77 piperidin-1-yl 3-CF₃-4-Cl-phenyl 78 piperazin-1-yl 3-CF₃-4-Cl-phenyl 79 4-methylpiperazin-1- 3-CF₃-4-Cl-phenyl yl 80 morpholin-4-yl 3-CF₃-4-Cl-phenyl 81 pyrrolidin-1-yl 3-methylphenyl 82 pyrrolin-1-yl 3-methylphenyl 83 imidazolidin-1-yl 3-methylphenyl 84 imidazolin-1-yl 3-methylphenyl 85 pyrazolidin-1-yl 3-methylphenyl 86 pyrazolin-1-yl 3-methylphenyl 87 piperidin-1-yl 3-methylphenyl 88 piperazin-1-yl 3-methylphenyl 89 4-methylpiperazin-1- 3-methylphenyl yl 90 morpholin-4-yl 3-methylphenyl 91 pyrrolidin-1-yl 3-methoxyphenyl 92 pyrrolin-1-yl 3-methoxyphenyl 93 imidazolidin-1-yl 3-methoxyphenyl 94 imidazolin-1-yl 3-methoxyphenyl 95 pyrazolidin-1-yl 3-methoxyphenyl 96 pyrazolin-1-yl 3-methoxyphenyl 97 piperidin-1-yl 3-methoxyphenyl 98 piperazin-1-yl 3-methoxyphenyl 99 4-methylpiperazin-1- 3-methoxyphenyl yl 100 morpholin-4-yl 3-methoxyphenyl 101 pyrrolidin-1-yl 3-ethylphenyl 102 pyrrolin-1-yl 3-ethylphenyl 103 imidazolidin-1-yl 3-ethylphenyl 104 imidazolin-1-yl 3-ethylphenyl 105 pyrazolidin-1-yl 3-ethylphenyl 106 pyrazolin-1-yl 3-ethylphenyl 107 piperidin-1-yl 3-ethylphenyl 108 piperazin-1-yl 3-ethylphenyl 109 4-methylpiperazin-1- 3-ethylphenyl yl 110 morpholin-4-yl 3-ethylphenyl 111 pyrrolidin-1-yl 3-isopropylphenyl 112 pyrrolin-1-yl 3-isopropylphenyl 113 imidazolidin-1-yl 3-isopropylphenyl 114 imidazolin-1-yl 3-isopropylphenyl 115 pyrazolidin-1-yl 3-isopropylphenyl 116 pyrazolin-1-yl 3-isopropylphenyl 117 piperidin-1-yl 3-isopropylphenyl 118 piperazin-1-yl 3-isopropylphenyl 119 4-methylpiperazin-1- 3-isopropylphenyl yl 120 morpholin-4-yl 3-isopropylphenyl

The compounds which comprise Category I of the present invention can be prepared by the procedure outlined herein below in Scheme I.

Example 1 N²-(3-chlorophenyl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine (4)

Preparation of 2-(methylthio)pyrimidine-4(3H)-one (1): To a solution of sodium hydroxide (6.24 g, 156.07 mmol) in H₂O (55 mL) at room temperature is added thiouridine (10 g, 78.03 mmol). The resulting mixture is stirred at room temperature for 20 min. Methyl iodide (5.45 mL, 87.40 mmol) in THF (10 mL) is added dropwise slowly and the mixture is stirred at room temperature for 18 hours. A white solid forms upon acidifying the mixture to pH 5 with glacial acetic acid. The mixture is allowed to stand at 0° C. (ice bath) for 2 hours and filtered to afford 7.4 g (67% yield) of the desired compound as a white solid. ¹H NMR (DMSO-d₆, 300 MHz): δ 2.45 (s, 3H), 6.07 (d, J=6.6 Hz, 1H), 7.85 (d, J=6.6 Hz, 1H).

Preparation of 2-(3-chlorophenylamino)pyrimidin-4(3H)-one (2): To 2-(methylthio)pyrimidine-4(3H)-one, 1, (4.88 g, 34.37 mmol) in diglyme (20 mL) is added 3-chloroaniline (4.3 mL, 68.74 mmol). The resulting mixture is heated to reflux and stirred for 18 hours. A solid forms upon cooling the mixture to room temperature. The solid is washed with hexanes to afford 5.0 g (66% yield) of the desired compound. ¹H NMR (DMSO-d₆, 300 MHz): δ 5.91 (d, J=5.7 Hz, 2H), 7.05 (d, J=7.5 Hz, 1H), 7.11 (br s, 1H), 7.32 (t, J=7.8, 15.9 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.86 (d, J=4.5 Hz, 1H), 7.94 (s, 1H).

Preparation of 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (3): To a 2-(substituted or unsubstituted phenylamino)pyrimidin-4(3H)-one (3.00 g, 13.5 mmol) in toluene (30 mL) is added N,N-dimethyl-aniline (3.57 mL, 28.4 mmol) and phosphorus oxychloride (1.24 mL, 13.5 mmol). The resulting mixture is heated to reflux for 15 minutes, cooled to room temperature and neutralized to pH 7 with 1M NaOH (aqueous). The organic layer is extracted with EtOAc (3×250 mL). The combined organic layers are dried (MgSO₄) and concentrated in vacuo. The residue is purified over silica (5% EtOAc in hexanes) to afford 2.0 g (61% yield) of the desired compound. ¹H NMR (DMSO-d₆, 300 MHz): δ 7.06-7.04 (m, 2H), 7.34 (t, J=8.1, 1H), 7.65-7.61 (m, 1H), 7.93 (m, 1H), 8.50 (d, J=5.1 Hz, 1H), 10.26 (s, 1H).

Preparation of N²-(3-chlorophenyl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine (4): To 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine, 3, (0.2 g, 0.84 mmol) in THF (4 mL) is added diisopropylethylamine (0.29 mL, 1.67 mmol) followed by 3-morpholino-propylamine (0.245 mL, 1.67 mmol). The resulting mixture was heated to reflux for 6 hours. Another 2 equivalents of 3-morpholinopropylamine (0.245 mL, 1.67 mmol) is added and the reaction heated to reflux and stirred for 18 hours. The resulting mixture is heated to reflux for 18 hours. The reaction is cooled to room temperature and concentrated in vacuo. The residue is diluted with 5 mL water and extracted with EtOAc (3×25 mL). The combined organic layers are dried (MgSO₄) and concentrated in vacuo. The residue is diluted with 5 mL water and extracted with EtOAc (3×25 mL). The combined organic layers are dried (MgSO₄) and concentrated in vacuo. This residue is purified over silica (6% MeOH in CH₂Cl₂ with 0.7% Et₃N) to afford 0.120 g (41% yield) of the desired compound. ¹H NMR (DMSO-d₆, 300 MHz): δ 1.68-1.75 (m, 2H), 2.34-2.40 (m, 6H), 3.30-3.35 (m, 2H), 3.55-3.58 (m, 4H), 5.97 (d, J=5.7 Hz, 1H), 6.88 (d, J=7.2 Hz, 1H), 7.19-7.28 (m, 2H), 7.59 (d, J=7.2 Hz, 1H), 7.80 (br s, 1H), 8.13 (br s, 1H), 9.19 (br s, 1H). MS (ESI, pos. ion) m/z: 348 (M+1).

The following are non-limiting examples of compounds which comprise first aspect of Category I of the present invention, the characterization of which will assist the formulator in establishing the chemical formulae of compounds which are not specifically exemplified herein. Alternatively, these compounds may also be synthesized by the synthetic route or methods described later in Scheme II.

N²-(3-Fluorophenyl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine: ¹H NMR (CDCl₃, 300 MHz) δ 1.83 (q, J=6.3 Hz, 2H), 2.47-2.57 (m, 6H), 3.47 (bs, 2H), 3.78 (t, J=4.8 Hz, 1H), 5.88 (d, J=6.0 Hz, 1H), 6.68 (tt, J=3.3, 1.0 Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 7.20 (t, J=6.3 Hz, 1H), 7.70 (bs, 1H), 7.81 (dt, J=12.0, 2.4 Hz, 1H), 7.96 (d, J=5.4 Hz, 1H); HRMS calcd for C₁₇H₂₂FN₅O, 332.1887 m/z (M+H)⁺; observed 332.1887 m/z.

N²-(3-Nitrophenyl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine. Yield 96 mg (66%) ¹H NMR (CDCl₃, 300 MHz): δ 1.87 (m, 2H), 2.54 (m, 6H), 3.59 (s, 2H), 3.77 (t, J=4.5 Hz, 4H), 5.94 (d, J=6.0 Hz, 1H), 6.37 (m, 1H), 7.42 (t, J=8.1 Hz, 1H), 7.67 (m, 1H), 7.81 (m, 1H), 7.91 (s, 1H), 7.97 (d, J=5.1 Hz, 1H). HRMS calcd for C17H22N6O3, 343.1882 m/z (M+H)⁺; observed 343.1895 m/z.

N²-(3-Bromophenyl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine. ¹H NMR (CDCl₃, 300 MHz): δ 1.84 (m, 2H), 2.53 (m, 6H), 3.49 (bs, 2H), 3.78 (t, J=4.8 Hz, 4H), 5.88 (d, J=6.0 Hz, 1H), 6.318 (bs, 1H), 7.13 (m, 3H), 7.38 (d, J=7.2 Hz, 1H), 7.94 (d, J=4.8 Hz, 1H), 8.12 (s, 1H). HRMS calcd for C17H22N5OBr, 392.1086 m/z (M+H)⁺; observed 392.1090 m/z.

N²-(3-Aminophenyl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine. ¹H NMR (CDCl₃, 300 MHz): δ 1.83 (m, 2H), 2.52 (m, 6H), 3.45 (m, 2H), 3.71 (bs, 2H), 3.79 (t, J=4.5 Hz, 4H), 5.83 (d, J=6.0 Hz, 1H), 6.12 (bs, 1H), 6.35 (m, 1H), 6.87 (s, 1H), 6.94 (m, 1H), 7.09 (t, J=8.1 Hz, 1H), 7.19 (t, J=2.4 Hz, 1H), 7.93 (d, J=6.0 Hz, 1H). HRMS calcd for C₁₇H₂₄N₆O, 329.2090 m/z (M+H)⁺; observed 329.2085 m/z.

{3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}-methanol: ¹H NMR (CDCl₃, 300 MHz) δ 1.72 (q, J=7.2 Hz, 2H), 2.30-2.41 (m, 6H), 3.30-3.38 (m, 2H), 3.58 (t, J=4.5 Hz, 4H), 4.45 (d, J=4.8 Hz, 2H), 5.10 (t, J=5.7 Hz, 1H), 5.92 (d, J=5.7 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H), 7.16 (t, J=7.8 Hz, 2H), 7.62 (d, J=7.2 Hz, 1H), 7.80 (bs, 2H), 8.90 (s, 1H); HRMS calcd for C₁₈H₂₅N₅O₂, 344.2087 m/z (M+H)⁺; observed 344.2084 m/z.

N²-(3-Phenoxyphenyl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine. ¹H NMR (DMSO-d6, 300 MHz): δ 1.62 (m, 2H), 2.31 (m, 6H), 2.52 (s, 2H), 3.56 (m, 4H), 5.92 (d, J=5.7 Hz, 1H), 6.51 (d, J=8.1 Hz, 1H), 6.99 (d, J=8.1 Hz, 2H), 7.10 (t, J=8.1 Hz, 1H), 7.21 (m, 2H), 7.37 (m, 2H), 7.80 (m, 1H), 9.10 (bs, 1H). HRMS calcd for C₂₃H₂₇N₅O₂, 406.2243 m/z (M+H)⁺; observed 406.2252 m/z.

N²-(3-Chlorophenyl)-N⁴-[3-(4-methylpiperazin-1-yl)-propyl]-pyrimidine-2,4-diamine: ¹H NMR (DMSO-d₆, 300 MHz): δ1.65-1.74 (m, 2H), 2.14 (s, 3H), 2.30-2.38 (m, 10H), 3.32-3.34 (m, 2H), 5.97 (d, J=5.7 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 7.2 (t, J=8.1 Hz, 1H), 7.28 (br s, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.80 (br s, 1H), 8.12 (br s, 1H), 9.19 (s, 1H). MS (ESI, pos. ion) m/z: 361 (M+1).

N²-(4-(Benzyloxy)-3-chlorophenyl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine. Yield 118 mg (46%) ¹H NMR (CDCl₃, 300 MHz): δ 1.89 (m, 6H), 2.64 (m, 4H), 2.70 (t, J=6.6 Hz, 2H), 3.49 (m, 2H), 5.15 (s, 2H), 5.84 (d, J=5.7 Hz, 1H), 6.20 (s, 1H), 7.25 (m, 1H), 7.41 (m, 3H), 7.49 (m, 2H), 7.90 (m, 2H). HRMS calcd for C₂₄H₂₈N₅OCl, 438.2061 m/z (M+H)⁺; observed 438.2077 m/z.

N²-(3-Nitrophenyl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine. ¹H NMR (DMSO-d6, 300 MHz): δ 1.87 (m, 2H), 2.01 (m, 4H), 3.00 (m, 2H), 3.22 (m, 2H), 3.55 (m, 4H), 6.29 (d, J=6.6 Hz, 1H), 7.68 (t, J=8.4 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.968 (m, 2H), 8.98 (s, 1H). HRMS calcd for C₁₇H₂₂N₆O₂, 343.1882 m/z (M+H)⁺; observed 343.1895 m/z.

N²-(3-Chlorophenyl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine. ¹H NMR (DMSO-d6, 300 MHz): δ 1.71 (m, 6H), 2.50 (m, 6H), 3.37 (m, 3H), 5.98 (d, J=5.7 Hz, 1H), 6.90 (d, J=9.0 Hz, 1H), 7.22 (t, J=8.1 Hz, 1H), 7.30 (s, 1H), 7.61 (d, J=8.1 Hz, 1H), 8.15 (s, 1H), 9.2 (s, 1H). HRMS calcd for C₁₇H₂₂N₅Cl, 332.1642 m/z (M+H)⁺; observed 332.1655 m/z.

N²-(3-Methylphenyl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine: ¹H NMR (DMSO-d6, 300 MHz) δ 1.78-2.06 (m, 6H), 2.35 (s, 3H), 2.85-3.00 (m, 2H), 3.10-3.18 (m, 2H), 3.40-3.55 (m, 4H), 6.27 (d, J=7.5 Hz, 1H), 7.02 (d, J=7.2 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.37-7.42 (m, 2H), 7.84 (d, J=7.2 Hz, 1H), 9.34 (bs, 1H), 10.59 (s, 1H), 10.77 (bs, 1H); HRMS calcd for C₁₈H₂₇N₅Cl, 312.2188 m/z (M+H)⁺; observed 312.2191 m/z.

N²-[3-Methoxyphenyl]-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine: ¹H NMR (DMSO-d6, 300 MHz) δ 1.80-2.10 (m, 6H), 2.87-3.02 (m, 2H), 3.10-3.20 (m, 2H), 3.40-3.55 (m, 4H), 3.79 (s, 3H), 6.27 (d, J=7.2 Hz, 1H), 6.76 (d, J=8.1 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.28-7.34 (m, 2H), 7.85 (d, J=7.2 Hz, 1H), 9.29 (bs, 1H), 10.60 (s, 1H), 10.78 (bs, 1H); HRMS calcd for C₁₈H₂₅N₅O, 328.2137 m/z (M+H)⁺; observed 328.2149 m/z.

N²-[3-Trifluoromethyl-phenyl]-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine ¹H NMR (DMSO-d6, 300 MHz) δ 1.77-2.04 (m, 6H), 2.83-3.00 (m, 2H), 3.03-3.20 (m, 2H), 3.31-3.70 (m, 4H), 6.32 (d, J=6.3 Hz, 1H), 7.50 (d, J=7.2 Hz, 1H), 7.65 (t, J=6.6 Hz, 1H), 7.8 (d, J=7.0 Hz, 1H), 7.89 (d, J=7.0 Hz, 1H), 8.15 (s, 1H), 9.40 (bs, 1H), 10.73 (bs, 1H), 11.00 (s, 1H); HRMS calcd for C₁₈H₂₄N₅F₃Cl, 366.1906 m/z (M+H)⁺; observed 366.1906 m/z.

N²-(3-Chlorophenyl)-N⁴-[3-(1-methylpiperidin-4-yl)-methyl]-pyrimidine-2,4-diamine hydrochloride. ¹H NMR (CD₃OD, 300 MHz): δ 1.53-1.58 (m, 2H), 2.04-2.09 (m, 3H), 2.87 (s, 3H), 2.98-3.05 (m, 2H), 3.46-3.59 (m, 4H), 6.31 (d, 1H, J=7.2 Hz), 7.27-7.48 (m, 3H), 7.25 (d, 1H, J=7.2 Hz), 7.83 (s, 1H). MS (ESI, pos. ion) m/z: 332 (M+1).

N²-(3-Isopropylphenyl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine: ¹H NMR (CDCl₃, 300 MHz): δ(ppm) 1.20 (d, J=2.1 Hz, 3H), 1.22 (d, J=2.1 Hz, 3H), 1.69-1.77 (m, 2H), 2.34-2.37 (m, 6H), 2.78-2.85 (m, 1H), 3.34 (m, 2H), 3.55-3.58 (m, 4H), 5.91 (d, J=6.0 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 7.09-7.15 (m, 2H), 7.53 (bs, 1H), 7.77 (bs, 2H), 8.84 (s, 1H). HRMS calcd for C₂₀H₂₉N₅O, 356.2450, m/z (M+H)⁺; observed 356.2463 m/z.

N²-(3,5-Bis-trifluoromethyl-phenyl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine: ¹H NMR (CD₃OD, 300 MHz) δ 2.12-2.22 (m, 2H), 3.13-3.27 (m, 4H), 3.49 (d, J=12.3 Hz, 2H), 3.65 (t, J=6.3 Hz, 2H), 3.83 (t, J=12.3 Hz, 2H), 4.07 (d, J=12.3 Hz, 2H), 6.43 (d, J=7.2 Hz, 1H), 7.83 (d, J=7.2 Hz, 1H), 7.85 (s, 1H), 8.32 (s, 2H); HRMS calcd for C₁₉H₂₁F₆N₅O, 450.1729 m/z (M+H)⁺; observed 450.1743 m/z.

N⁴-(3-Morpholin-4-yl-propyl)-N²-(3-trifluoromethoxy-phenyl)-pyrimidine-2,4-diamine: MS (ESI, pos. ion) m/z: 398 (M+1).

N⁴-(3-Morpholin-4-yl-propyl)-N²-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-pyrimidine-2,4-diamine: MS (ESI, pos. ion) m/z: 430 (M+1).

Further compounds which are encompassed within the first aspect of Category I of the present invention but which are not fully exemplified include:

-   N²-(3-Chlorophenyl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Chlorophenyl)-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Chlorophenyl)-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Chlorophenyl)-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Chlorophenyl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Fluorophenyl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Fluorophenyl)-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Fluorophenyl)-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Fluorophenyl)-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Fluorophenyl)-N⁴-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Fluorophenyl)-N⁴-(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Fluorophenyl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Methylphenyl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Methylphenyl)-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Methylphenyl)-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Methylphenyl)-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Methylphenyl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Methylphenyl)-N⁴-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Methylphenyl)-N⁴-(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Methoxyphenyl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Methoxyphenyl)-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Methoxyphenyl)-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Methoxyphenyl)-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Methoxyphenyl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Methoxyphenyl)-N⁴-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Methoxyphenyl)-N⁴-(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Trifluoromethylphenyl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Trifluoromethylphenyl)-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Trifluoromethylphenyl)-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Trifluoromethylphenyl)-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Trifluoromethylphenyl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3-Trifluoromethylphenyl)-N⁴-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine;     and -   N²-(3-Trifluoromethylphenyl)-N⁴-(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine.

The compounds which comprise the second aspect of Category I of the present invention are 2,4-di-aminopyrimidines having the formula:

wherein R¹ phenyl units are substituted by one or more R⁵ units chosen from:

-   -   x) substituted or unsubstituted C₃-C₉ heteroaryl units;         which are further exemplified herein below in Table II.

TABLE II No R R¹ 121 pyrrolidin-1-yl 2-(pyridin-2-yl)phenyl 122 pyrrolin-1-yl 2-(pyridin-2-yl)phenyl 123 imidazolin-1-yl 2-(pyridin-2-yl)phenyl 124 imidazolin-1-yl 2-(pyridin-2-yl)phenyl 125 pyrazolidin-1-yl 2-(pyridin-2-yl)phenyl 126 pyrazolin-1-yl 2-(pyridin-2-yl)phenyl 127 piperidin-1-yl 2-(pyridin-2-yl)phenyl 128 piperazin-1-yl 2-(pyridin-2-yl)phenyl 129 4-methylpiperazin-1- 2-(pyridin-2-yl)phenyl yl 130 morpholin-4-yl 2-(pyridin-2-yl)phenyl 131 pyrrolidin-1-yl 2-(pyridin-3-yl)phenyl 132 pyrrolin-1-yl 2-(pyridin-3-yl)phenyl 133 imidazolidin-1-yl 2-(pyridin-3-yl)phenyl 134 imidazolin-1-yl 2-(pyridin-3-yl)phenyl 135 pyrazolidin-1-yl 2-(pyridin-3-yl)phenyl 136 pyrazolin-1-yl 2-(pyridin-3-yl)phenyl 137 piperidin-1-yl 2-(pyridin-3-yl)phenyl 138 piperazin-1-yl 2-(pyridin-3-yl)phenyl 139 4-methylpiperazin-1- 2-(pyridin-3-yl)phenyl yl 140 morpholin-4-yl 2-(pyridin-4-yl)phenyl 141 pyrrolidin-1-yl 2-(pyridin-4-yl)phenyl 142 pyrrolin-1-yl 2-(pyridin-4-yl)phenyl 143 imidazolidin-1-yl 2-(pyridin-4-yl)phenyl 144 imidazolin-1-yl 2-(pyridin-4-yl)phenyl 145 pyrazolidin-1-yl 2-(pyridin-4-yl)phenyl 146 pyrazolin-1-yl 2-(pyridin-4-yl)phenyl 147 piperidin-1-yl 2-(pyridin-4-yl)phenyl 148 piperazin-1-yl 2-(pyridin-4-yl)phenyl 149 4-methylpiperazin-1- 2-(pyridin-4-yl)phenyl yl 150 morpholin-4-yl 2-(pyridin-4-yl)phenyl 151 pyrrolidin-1-yl 3-(pyridin-2-yl)phenyl 152 pyrrolin-1-yl 3-(pyridin-2-yl)phenyl 153 imidazolidin-1-yl 3-(pyridin-2-yl)phenyl 154 imidazolin-1-yl 3-(pyridin-2-yl)phenyl 155 pyrazolidin-1-yl 3-(pyridin-2-yl)phenyl 156 pyrazolin-1-yl 3-(pyridin-2-yl)phenyl 157 piperidin-1-yl 3-(pyridin-2-yl)phenyl 158 piperazin-1-yl 3-(pyridin-2-yl)phenyl 159 4-methylpiperazin-1- 3-(pyridin-2-yl)phenyl yl 160 morpholin-4-yl 3-(pyridin-2-yl)phenyl 161 pyrrolidin-1-yl 3-(pyridin-3-yl)phenyl 162 pyrrolin-1-yl 3-(pyridin-3-yl)phenyl 163 imidazolidin-1-yl 3-(pyridin-3-yl)phenyl 164 imidazolin-1-yl 3-(pyridin-3-yl)phenyl 165 pyrazolidin-1-yl 3-(pyridin-3-yl)phenyl 166 pyrazolin-1-yl 3-(pyridin-3-yl)phenyl 167 piperidin-1-yl 3-(pyridin-3-yl)phenyl 168 piperazin-1-yl 3-(pyridin-3-yl)phenyl 169 4-methylpiperazin-1- 3-(pyridin-3-yl)phenyl yl 170 morpholin-4-yl 3-(pyridin-4-yl)phenyl 171 pyrrolidin-1-yl 3-(pyridin-4-yl)phenyl 172 pyrrolin-1-yl 3-(pyridin-4-yl)phenyl 173 imidazolidin-1-yl 3-(pyridin-4-yl)phenyl 174 imidazolin-1-yl 3-(pyridin-4-yl)phenyl 175 pyrazolidin-1-yl 3-(pyridin-4-yl)phenyl 176 pyrazolin-1-yl 3-(pyridin-4-yl)phenyl 177 piperidin-1-yl 3-(pyridin-4-yl)phenyl 178 piperazin-1-yl 3-(pyridin-4-yl)phenyl 179 4-methylpiperazin-1- 3-(pyridin-4-yl)phenyl yl 180 morpholin-4-yl 3-(pyridin-4-yl)phenyl 181 pyrrolidin-1-yl 4-(pyridin-2-yl)phenyl 182 pyrrolin-1-yl 4-(pyridin-2-yl)phenyl 183 imidazolidin-1-yl 4-(pyridin-2-yl)phenyl 184 imidazolin-1-yl 4-(pyridin-2-yl)phenyl 185 pyrazolidin-1-yl 4-(pyridin-2-yl)phenyl 186 pyrazolin-1-yl 4-(pyridin-2-yl)phenyl 187 piperidin-1-yl 4-(pyridin-2-yl)phenyl 188 piperazin-1-yl 4-(pyridin-2-yl)phenyl 189 4-methylpiperazin-1- 4-(pyridin-2-yl)phenyl yl 190 morpholin-4-yl 4-(pyridin-2-yl)phenyl 191 pyrrolidin-1-yl 4-(pyridin-3-yl)phenyl 192 pyrrolin-1-yl 4-(pyridin-3-yl)phenyl 193 imidazolidin-1-yl 4-(pyridin-3-yl)phenyl 194 imidazolin-1-yl 4-(pyridin-3-yl)phenyl 195 pyrazolidin-1-yl 4-(pyridin-3-yl)phenyl 196 pyrazolin-1-yl 4-(pyridin-3-yl)phenyl 197 piperidin-1-yl 4-(pyridin-3-yl)phenyl 198 piperazin-1-yl 4-(pyridin-3-yl)phenyl 199 4-methylpiperazin-1- 4-(pyridin-3-yl)phenyl yl 200 morpholin-4-yl 4-(pyridin-4-yl)phenyl 201 pyrrolidin-1-yl 4-(pyridin-4-yl)phenyl 202 pyrrolin-1-yl 4-(pyridin-4-yl)phenyl 203 imidazolidin-1-yl 4-(pyridin-4-yl)phenyl 204 imidazolin-1-yl 4-(pyridin-4-yl)phenyl 205 pyrazolidin-1-yl 4-(pyridin-4-yl)phenyl 206 pyrazolin-1-yl 4-(pyridin-4-yl)phenyl 207 piperidin-1-yl 4-(pyridin-4-yl)phenyl 208 piperazin-1-yl 4-(pyridin-4-yl)phenyl 209 4-methylpiperazin-1- 4-(pyridin-4-yl)phenyl yl 210 morpholin-4-yl 4-(pyridin-4-yl)phenyl 211 pyrrolidin-1-yl 3-(pyrimidin-2-yl)phenyl 212 pyrrolin-1-yl 3-(pyrimidin-2-yl)phenyl 213 imidazolidin-1-yl 3-(pyrimidin-2-yl)phenyl 214 imidazolin-1-yl 3-(pyrimidin-2-yl)phenyl 215 pyrazolidin-1-yl 3-(pyrimidin-2-yl)phenyl 216 pyrazolin-1-yl 3-(pyrimidin-2-yl)phenyl 217 piperidin-1-yl 3-(pyrimidin-2-yl)phenyl 218 piperazin-1-yl 3-(pyrimidin-2-yl)phenyl 219 4-methylpiperazin-1- 3-(pyrimidin-2-yl)phenyl yl 220 morpholin-4-yl 3-(pyrimidin-2-yl)phenyl 221 pyrrolidin-1-yl 3-(pyrimidin-3-yl)phenyl 222 pyrrolin-1-yl 3-(pyrimidin-3-yl)phenyl 223 imidazolidin-1-yl 3-(pyrimidin-3-yl)phenyl 224 imidazolin-1-yl 3-(pyrimidin-3-yl)phenyl 225 pyrazolidin-1-yl 3-(pyrimidin-3-yl)phenyl 226 pyrazolin-1-yl 3-(pyrimidin-3-yl)phenyl 227 piperidin-1-yl 3-(pyrimidin-3-yl)phenyl 228 piperazin-1-yl 3-(pyrimidin-3-yl)phenyl 229 4-methylpiperazin-1- 3-(pyrimidin-3-yl)phenyl yl 230 morpholin-4-yl 3-(pyrimidin-4-yl)phenyl 231 pyrrolidin-1-yl 3-(pyrimidin-4-yl)phenyl 232 pyrrolin-1-yl 3-(pyrimidin-4-yl)phenyl 233 imidazolidin-1-yl 3-(pyrimidin-4-yl)phenyl 234 imidazolin-1-yl 3-(pyrimidin-4-yl)phenyl 235 pyrazolidin-1-yl 3-(pyrimidin-4-yl)phenyl 236 pyrazolin-1-yl 3-(pyrimidin-4-yl)phenyl 237 piperidin-1-yl 3-(pyrimidin-4-yl)phenyl 238 piperazin-1-yl 3-(pyrimidin-4-yl)phenyl 239 4-methylpiperazin-1- 3-(pyrimidin-4-yl)phenyl yl 240 morpholin-4-yl 3-(pyrimidin-4-yl)phenyl

The compounds which comprise the second aspect of Category I of the present invention can be prepared by the procedure outlined herein below in Scheme II and Example 2.

Example 2 N²-[3-(Pyridin-3-yl)-phenyl]-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine (7)

Preparation of 2-chloro-N-(3-morpholinopropyl)pyrimidin-4-amine (5): To 2,4-dichloropyrimidine (5.0 g, 33.5 mmol), diisoproylethylamine (5.85 ml, 33.5 mmol) in 50 ml of a 1:1 mixture of n-butanol and water is added 3-morpholinopropan-1-amine (4.90 ml, 33.5 mmol). The resulting mixture was stirred for 18 hours at room temperature. The mixture is then concentrated in vacuo, diluted with 30 mL water and extracted with EtOAc (3×50 ml). Combined organic layers are washed with saturated NaHCO₃ (2×20 ml) and saturated NaCl (2×20 ml), then dried over magnesium sulfate. The residue is purified over silica (25% EtOAc in Hexanes) to afford 4.5 g (51% yield) of the desired product. ¹H NMR (CDCl₃, 300 MHz): δ(ppm) 1.83 (q, J=2.0 Hz, 2H), 2.54 (m, 6H), 3.53 (bs, 2H), 3.79 (t, J=4.7 Hz, 4H), 6.24 (d, J=5.67 Hz, 1H), 6.92 (bs, 1H), 7.99 (bs, 1H). MS (ESI, pos. ion) m/z: 257 (M+1).

Preparation of 3-(pyridin-3-yl)benzenamine (6): To 3-bromoaniline (513.1 mg, 2.983 mmol) was added ethanol/toluene (1:1, 20 mL), 3-pyridinylboronic acid (397.3 mg, 3.232 mmol), sodium carbonate (1.85 g, 17.45 mmol) in 9 mL water, and tetrakis(triphenylphosphine)palladium (504.3 mg, 0.439 mmol). The resulting mixture is heated to 80° C. and stirred for 16 h. The reaction mixture is cooled, diluted with 10 mL of water and extracted with EtOAc (3×25 ml). The organics were combined and, washed with 10 mL of water and saturated aqueous NaCl (2×10 mL), then dried over magnesium sulfate and concentrated in vacuo to a brown oil. The oil is purified over silica (0-5% MeOH in CH₂Cl₂) to afford 345 mg (68% yield) of the desired compound. MS (ESI, pos. ion) m/z: 171 (M+1).

Preparation of N²-(3-(pyridin-3-yl)-phenyl)-N⁴-(3-morpholin-4-yl-propyl)pyrimidine-2,4-diamine(7): To 2-chloro-N-(3-morpholinopropyl)pyrimidin-4-amine, 5, (105.7 mg, 0.4117 mmol) in 3 mL of EtOH/water (1:1) is added 3-(pyridin-3-yl)benzenamine (84.0 mg, 0.4941 mmol) and 2 drops concentrated HCl. The resulting mixture is heated to 80° C. with stirring for 3 days. The reaction mixture is cooled to room temperature and concentrated in vacuo. The product was diluted with 5 mL of aqueous saturated sodium bicarbonate solution and extracted with EtOAc (3×10 ml). The combined organics are washed with 20 ml water and saturated aqueous NaCl (2×10 ml), then dried over magnesium sulfate and concentrated in vacuo. The residue is purified over silica (5-8% MeOH in CH₂Cl₂) to afford 61 mg (38% yield) of the desired compound. ¹H NMR (DMSO-d₆, 300 MHz): δ 1.63-1.77 (m, 2H), 2.20-2.40 (m, 6H), 3.30-3.47 (m, 2H), 3.54 (t, J=4.2 Hz, 4H), 5.96 (d, J=5.4 Hz, 1H), 7.12-7.28 (m, 2H), 7.36 (t, J=7.8 Hz, 1H), 7.50 (dd, J=4.8, 7.8 Hz, 1H), 7.78 (bs, 1H), 7.82 (d, J=7.8 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 8.29 (bs, 1H), 8.58 (d, J=4.8 Hz, 1H), 8.85 (s, 1H), 9.10 (s, 1H). HRMS calcd for C₂₂H₂₆N₆O, 391.2246 m/z (M+H)⁺; observed 391.2242 m/z.

The following are non-limiting examples of compounds which comprise the second aspect of Category I of the present invention, the characterization of which will assist the formulator in establishing the chemical formulae of compounds which are not specifically exemplified herein. Alternatively, these compounds may also be synthesized by the synthetic route or methods described earlier in Scheme I.

N²-[3-(Benzo[d]thiazol-2-yl)-phenyl]-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine. ¹H NMR (DMSO-d6, 300 MHz): δ 1.71-1.76 (m, 2H), 2.25-2.34 (m, 6H), 2.52 (s, 2H), 3.51 (m, 4H), 6.00 (d, J=6.0 Hz, 1H), 7.29 (bs, 1H), 7.45 (m, 2H), 7.54 (m, 2H), 7.84 (m, 1H), 8.06 (d, J=8.1 Hz, 1H), 8.15 (d, J=7.5 Hz, 1H), 8.86 (bs, 1H), 9.28 (s, 1H). HRMS calcd for C₂₄H₂₆N₆OS, 447.1967 m/z (M+H)⁺; observed 447.1976 m/z.

N²-[3-(1H-Indol-2-yl)-phenyl]-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine: HRMS calcd for C₂₅H₂₈N₆O, 429.2397 m/z (M+H)⁺; observed 429.2395 m/z.

N²-[3-(1H-Indol-4-yl)-phenyl]-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine: HRMS calcd for C₂₅H₂₉N₆O, 429.2397 m/z (M+H)⁺; observed 429.2406 m/z.

N²-[3-(Pyridin-4-yl)-phenyl]-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine: HRMS calcd for C₂₂H₂₇N₆O, 391.2246 m/z (M+H)⁺; observed 391.2255 m/z.

N²-[3-(1H-Indol-6-yl)-phenyl]-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine: HRMS calcd for C₂₅H₂₉N₆O, 429.2403 m/z (M+H)⁺; observed 429.2412 m/z.

Further compounds which are encompassed within the second aspect of Category II of the present invention but which are not fully exemplified include:

-   N²-[3-(Pyridin-2-yl)-phenyl]-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-3-yl)-phenyl]-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-2-yl)-phenyl]-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-3-yl)-phenyl]-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Benzo[d]thiazol-2-yl)-phenyl]-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-2-yl)-phenyl]-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-4-yl)-phenyl]-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-2-yl)-phenyl]-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-3-yl)-phenyl]-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Benzo[d]thiazol-2-yl)-phenyl]-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-2-yl)-phenyl]-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-4-yl)-phenyl]-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-2-yl)-phenyl]-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-3-yl)-phenyl]-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Benzo[d]thiazol-2-yl)-phenyl]-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-2-yl)-phenyl]-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-4-yl)-phenyl]-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-2-yl)-phenyl]-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-3-yl)-phenyl]-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Benzo[d]thiazol-2-yl)-phenyl]-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-2-yl)-phenyl]-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-4-yl)-phenyl]-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-2-yl)-phenyl]-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-3-yl)-phenyl]-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Benzo[d]thiazol-2-yl)-phenyl]-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-2-yl)-phenyl]-N⁴-(3-pyrazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-4-yl)-phenyl]-N⁴-(3-pyrazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-2-yl)-phenyl]-N⁴-(3-pyrazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-3-yl)-phenyl]-N⁴-(3-pyrazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Benzo[d]thiazol-2-yl)-phenyl]-N⁴-(3-pyrazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-2-yl)-phenyl]-N⁴-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-4-yl)-phenyl]-N⁴-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-2-yl)-phenyl]-N⁴-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-3-yl)-phenyl]-N⁴-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Benzo[d]thiazol-2-yl)-phenyl]-N⁴-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-2-yl)-phenyl]-N⁴-(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-4-yl)-phenyl]-N⁴-(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-2-yl)-phenyl]-N⁴-(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-3-yl)-phenyl]-N⁴-(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Benzo[d]thiazol-2-yl)-phenyl]-N⁴-(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-2-yl)-phenyl]-N⁴-[3-(4-methylpiperazin-1-yl)-propyl]-pyrimidine-2,4-diamine; -   N²-[3-(Pyridin-4-yl)-phenyl]-N⁴-[3-(4-methylpiperazin-1-yl)-propyl]-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-2-yl)-phenyl]-N⁴-[3-(4-methylpiperazin-1-yl)-propyl]-pyrimidine-2,4-diamine; -   N²-[3-(1H-Indol-3-yl)-phenyl]-N⁴-[3-(4-methylpiperazin-1-yl)-propyl]-pyrimidine-2,4-diamine;     and -   N²-[3-(Benzo[d]thiazol-2-yl)-phenyl]-N⁴-[3-(4-methylpiperazin-1-yl)-propyl]-pyrimidine-2,4-diamine.

The third aspect of Category I of the present invention are 2,4-di-aminopyrimidines having the formula:

wherein R¹ phenyl units are substituted by one or more R⁵ units chosen from:

-   -   viii) substituted or unsubstituted phenyl;         which are further exemplified herein below in Table III.

TABLE III No R R¹ 241 pyrrolidin-1-yl biphenyl-3-yl 242 pyrrolin-1-yl biphenyl-3-yl 243 imidazolidin-1-yl biphenyl-3-yl 244 imidazolin-1-yl biphenyl-3-yl 245 pyrazolidin-1-yl biphenyl-3-yl 246 pyrazolin-1-yl biphenyl-3-yl 247 piperidin-1-yl biphenyl-3-yl 248 piperazin-1-yl biphenyl-3-yl 249 4-methylpiperazin-1- biphenyl-3-yl yl 250 morpholin-4-yl biphenyl-3-yl 251 pyrrolidin-1-yl biphenyl-4-yl 252 pyrrolin-1-yl biphenyl-4-yl 253 imidazolidin-1-yl biphenyl-4-yl 254 imidazolin-1-yl biphenyl-4-yl 255 pyrazolidin-1-yl biphenyl-4-yl 256 pyrazolin-1-yl biphenyl-4-yl 257 piperidin-1-yl biphenyl-4-yl 258 piperazin-1-yl biphenyl-4-yl 259 4-methylpiperazin-1- biphenyl-4-yl yl 260 morpholin-4-yl biphenyl-4-yl 261 pyrrolidin-1-yl 4′-fluoro-biphenyl-3-yl 262 pyrrolin-1-yl 4′-fluoro-biphenyl-3-yl 263 imidazolidin-1-yl 4′-fluoro-biphenyl-3-yl 264 imidazolin-1-yl 4′-fluoro-biphenyl-3-yl 265 pyrazolidin-1-yl 4′-fluoro-biphenyl-3-yl 266 pyrazolin-1-yl 4′-fluoro-biphenyl-3-yl 267 piperidin-1-yl 4′-fluoro-biphenyl-3-yl 268 piperazin-1-yl 4′-fluoro-biphenyl-3-yl 269 4-methylpiperazin-1- 4′-fluoro-biphenyl-3-yl yl 270 morpholin-4-yl 4′-fluoro-biphenyl-3-yl 271 pyrrolidin-1-yl 4′-chloro-biphenyl-3-yl 272 pyrrolin-1-yl 4′-chloro-biphenyl-3-yl 273 imidazolidin-1-yl 4′-chloro-biphenyl-3-yl 274 imidazolin-1-yl 4′-chloro-biphenyl-3-yl 275 pyrazolidin-1-yl 4′-chloro-biphenyl-3-yl 276 pyrazolin-1-yl 4′-chloro-biphenyl-3-yl 277 piperidin-1-yl 4′-chloro-biphenyl-3-yl 278 piperazin-1-yl 4′-chloro-biphenyl-3-yl 279 4-methylpiperazin-1- 4′-chloro-biphenyl-3-yl yl 280 morpholin-4-yl 4′-chloro-biphenyl-3-yl

Example 3 N²-Biphenyl-3-yl-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine (10)

Preparation of 2-(3-biphenylamino)pyrimidin-4(3H)-one (8): To 2-(methylthio)-pyrimidine-4(3H)-one (790 mg, 5.5 mmol) in 5 mL of diglyme is added 3-amino-biphenyl (1.91 g, 11.2 mmol). The resulting mixture is stirred at reflux for 18 hours. The mixture is cooled to room temperature and hexanes are added to form a precipitate which is collected by filtration to afford 1.34 g (92% yield) of the desired compound which is used without purification. MS (ESI, pos. ion) m/z: 264 (M+1).

Preparation of 4-chloro-N-(3-biphenyl)pyrimidin-2-amine (9): To 2-(3-biphenylamino)pyrimidin-4(3H)-one (1.34 g, 5.0 mmol), and N,N-dimethylaniline (1.5 mL) is added 10 mL of phosphorus oxychloride. The resulting mixture is heated at reflux for 1 hour, cooled to room temperature and concentrated in vacuo. The residue is neutralized with 1M NaOH (aqueous). The organics are extracted t portions of EtOAc (2×50 mL). The combined organic layers are washed with brine, dried (MgSO₄), and concentrated in vacuo. The residue is purified over silica (5% EtOAc in hexanes) to afford 780 mg (54% yield) of the desired compound. MS (ESI, pos. ion) m/z: 282 (M+1).

Preparation of N²-biphenyl-3-yl-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine (10): To 4-chloro-N-(3-biphenyl)pyrimidin-2-amine (301.0 mg, 1.07 mmol) in 5 mL THF is added potassium carbonate (396 mg, 2.15 mmol) followed by 3-morpholinopropyl-amine (0.3 mL, 2.05 mmol). The resulting mixture is heated at reflux for 96 hours. The reaction is cooled to room temperature and concentrated in vacuo. The residue is diluted with 15 mL of water and extracted with EtOAc (3×20 mL). The combined organic layers are washed with water and brine, dried (MgSO₄) and concentrated in vacuo. The crude product is purified over silica (5% MeOH in CH₂Cl₂) to afford 362 mg (87% yield) of the desired compound. ¹H NMR (DMSO-d₆, 300 MHz): δ1.69 (m, 2H), 2.26-2.32 (m, 6H), 3.38 (m, 2H), 3.54 (t, J=4.2 Hz, 4H), 5.95 (d, J=6.0 Hz, 1H), 7.15 (d, J=7.5 Hz, 1H), 7.21 (bs, 1H), 7.29-7.39 (m, 2H), 7.47 (t, J=8.1 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H), 7.73 (bs, 1H), 7.81 (d, J=6.0 Hz, 1H), 8.23 (bs, 1H), 9.05 (s, 1H). MS (ESI, pos. ion) m/z: 390 (M+1).

The following are non-limiting examples of compounds which comprise the third aspect of Category I of the present invention, the characterization of which will assist the formulator in establishing the chemical formulae of compounds which are not specifically exemplified herein. Alternatively, these compounds may also be synthesized by the synthetic route or methods described earlier in Scheme II.

N²-(3′-Nitrobiphenyl-3-yl)-10-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine: ¹H NMR (CDCl₃, 300 MHz) δ 1.80-1.88 (m, 2H), 2.52 (t, J=4.5 Hz, 4H), 2.55 (t, J=6.3 Hz, 2H), 3.56 (bs, 2H), 3.76 (t, J=4.5 Hz, 4H), 5.90 (d, J=6.0 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 7.29 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.47 (bs, 1H), 7.58 (bs, 1H), 7.64 (t, J=7.5 Hz, 1H), 7.93 (d, J=6.0 Hz, 1H), 7.97 (d, J=7.5 Hz, 1H), 8.15 (bs, 1H), 8.23 (d, J=7.5 Hz, 1H), 8.52 (bs, 1H); HRMS calcd for C₂₃H₂₆N₆O₃, 435.2145 m/z (M+H)⁺; observed 435.2125 m/z.

Further compounds which are encompassed within the third aspect of Category II of the present invention but which are not fully exemplified include:

-   N²-(3′-Nitro-biphenyl-3-yl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Nitro-biphenyl-3-yl)-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Nitro-biphenyl-3-yl)-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Nitro-biphenyl-3-yl)-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Nitro-biphenyl-3-yl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Nitro-biphenyl-3-yl)-N⁴-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Nitro-biphenyl-3-yl)-N⁴-(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Nitro-biphenyl-3-yl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Chloro-biphenyl-3-yl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Chloro-biphenyl-3-yl)-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Chloro-biphenyl-3-yl)-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Chloro-biphenyl-3-yl)-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Chloro-biphenyl-3-yl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Chloro-biphenyl-3-yl)-N⁴-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Chloro-biphenyl-3-yl)-N⁴-(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Chloro-biphenyl-3-yl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Chloro-biphenyl-3-yl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Fluoro-biphenyl-3-yl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Fluoro-biphenyl-3-yl)-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Fluoro-biphenyl-3-yl)-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Fluoro-biphenyl-3-yl)-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Fluoro-biphenyl-3-yl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Fluoro-biphenyl-3-yl)-N⁴-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Fluoro-biphenyl-3-yl)-N⁴-(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Fluoro-biphenyl-3-yl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Fluoro-biphenyl-3-yl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methyl-biphenyl-3-yl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methyl-biphenyl-3-yl)-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methyl-biphenyl-3-yl)-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methyl-biphenyl-3-yl)-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methyl-biphenyl-3-yl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methyl-biphenyl-3-yl)-N⁴-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methyl-biphenyl-3-yl)-N⁴-(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methyl-biphenyl-3-yl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methyl-biphenyl-3-yl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methoxy-biphenyl-3-yl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methoxy-biphenyl-3-yl)-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methoxy-biphenyl-3-yl)-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methoxy-biphenyl-3-yl)-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methoxy-biphenyl-3-yl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methoxy-biphenyl-3-yl)-N⁴-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methoxy-biphenyl-3-yl)-N⁴-(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methoxy-biphenyl-3-yl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Methoxy-biphenyl-3-yl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Dimethylamino-biphenyl-3-yl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Dimethylamino-biphenyl-3-yl)-N⁴-(3-pyrrolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Dimethylamino-biphenyl-3-yl)-N⁴-(3-imidazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Dimethylamino-biphenyl-3-yl)-N⁴-(3-imidazolin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Dimethylamino-biphenyl-3-yl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Dimethylamino-biphenyl-3-yl)-N⁴-(3-piperidin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-[(-(3′-Dimethylamino-biphenyl-3-yl)-N⁴-(3-piperazin-1-yl-propyl)-pyrimidine-2,4-diamine; -   N²-(3′-Dimethylamino-biphenyl-3-yl)-N⁴-(3-pyrazolidin-1-yl-propyl)-pyrimidine-2,4-diamine;     and -   N²-(3′-Dimethylamino-biphenyl-3-yl)-N′-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine.

The compounds which comprise Category II of the present invention are 2,4-diaminopyrimidines having the formula:

wherein R is a heterocyclic unit attached to the core scaffold by way of a nitrogen atom and R¹ is a phenyl unit substituted by different category of R⁵ units having the formula:

-L¹-R⁶

and L¹ and R⁶ are further defined herein below in Table IV.

TABLE IV No R L¹ R⁶ 281 pyrrolidin-1-yl —SO₂NH— —H 282 pyrrolin-1-yl —SO₂NH— —H 283 imidazolidin-1-yl —SO₂NH— —H 284 imidazolin-1-yl —SO₂NH— —H 285 pyrazolidin-1-yl —SO₂NH— —H 286 pyrazolin-1-yl —SO₂NH— —H 287 piperidin-1-yl —SO₂NH— —H 288 piperazin-1-yl —SO₂NH— —H 289 4-methylpiperazin-1-yl —SO₂NH— —H 290 morpholin-4-yl —SO₂NH— —H 291 pyrrolidin-1-yl —SO₂NH— —CH₃ 292 pyrrolin-1-yl —SO₂NH— —CH₃ 293 imidazolidin-1-yl —SO₂NH— —CH₃ 294 imidazolin-1-yl —SO₂NH— —CH₃ 295 pyrazolidin-1-yl —SO₂NH— —CH₃ 296 pyrazolin-1-yl —SO₂NH— —CH₃ 297 piperidin-1-yl —SO₂NH— —CH₃ 298 piperazin-1-yl —SO₂NH— —CH₃ 299 4-methylpiperazin-1-yl —SO₂NH— —CH₃ 300 morpholin-4-yl —SO₂NH— —CH₃ 301 pyrrolidin-1-yl —SO₂NH— phenyl 302 pyrrolin-1-yl —SO₂NH— phenyl 303 imidazolidin-1-yl —SO₂NH— phenyl 304 imidazolin-1-yl —SO₂NH— phenyl 305 pyrazolidin-1-yl —SO₂NH— phenyl 306 pyrazolin-1-yl —SO₂NH— phenyl 307 piperidin-1-yl —SO₂NH— phenyl 308 piperazin-1-yl —SO₂NH— phenyl 309 4-methylpiperazin-1-yl —SO₂NH— phenyl 310 morpholin-4-yl —SO₂NH— phenyl 311 pyrrolidin-1-yl —SO₂NH— pyridin-3-yl 312 pyrrolin-1-yl —SO₂NH— pyridin-3-yl 313 imidazolidin-1-yl —SO₂NH— pyridin-3-yl 314 imidazolin-1-yl —SO₂NH— pyridin-3-yl 315 pyrazolidin-1-yl —SO₂NH— pyridin-3-yl 316 pyrazolin-1-yl —SO₂NH— pyridin-3-yl 317 piperidin-1-yl —SO₂NH— pyridin-3-yl 318 piperazin-1-yl —SO₂NH— pyridin-3-yl 319 4-methylpiperazin-1-yl —SO₂NH— pyridin-3-yl 320 morpholin-4-yl —SO₂NH— pyridin-3-yl 321 pyrrolidin-1-yl —NHC(O)— phenyl 322 pyrrolin-1-yl —NHC(O)— phenyl 323 imidazolidin-1-yl —NHC(O)— phenyl 324 imidazolin-1-yl —NHC(O)— phenyl 325 pyrazolidin-1-yl —NHC(O)— phenyl 326 pyrazolin-1-yl —NHC(O)— phenyl 327 piperidin-1-yl —NHC(O)— phenyl 328 piperazin-1-yl —NHC(O)— phenyl 329 4-methylpiperazin-1-yl —NHC(O)— phenyl 330 morpholin-4-yl —NHC(O)— phenyl 331 pyrrolidin-1-yl —NHC(O)— pyridin-3-yl 332 pyrrolin-1-yl —NHC(O)— pyridin-3-yl 333 imidazolidin-1-yl —NHC(O)— pyridin-3-yl 334 imidazolin-1-yl —NHC(O)— pyridin-3-yl 335 pyrazolidin-1-yl —NHC(O)— pyridin-3-yl 336 pyrazolin-1-yl —NHC(O)— pyridin-3-yl 337 piperidin-1-yl —NHC(O)— pyridin-3-yl 338 piperazin-1-yl —NHC(O)— pyridin-3-yl 339 4-methylpiperazin-1-yl —NHC(O)— pyridin-3-yl 340 morpholin-4-yl —NHC(O)— pyridin-3-yl 341 pyrrolidin-1-yl —C(O)NH— pyridin-3-yl 342 pyrrolin-1-yl —C(O)NH— pyridin-3-yl 343 imidazolidin-1-yl —C(O)NH— pyridin-3-yl 344 imidazolin-1-yl —C(O)NH— pyridin-3-yl 345 pyrazolidin-1-yl —C(O)NH— pyridin-3-yl 346 pyrazolin-1-yl —C(O)NH— pyridin-3-yl 347 piperidin-1-yl —C(O)NH— pyridin-3-yl 348 piperazin-1-yl —C(O)NH— pyridin-3-yl 349 4-methylpiperazin-1-yl —C(O)NH— pyridin-3-yl 350 morpholin-4-yl —C(O)NH— pyridin-3-yl 351 pyrrolidin-1-yl —CH₂CH₂— pyridin-3-yl 352 pyrrolin-1-yl —CH₂CH₂— pyridin-3-yl 353 imidazolidin-1-yl —CH₂CH₂— pyridin-3-yl 354 imidazolin-1-yl —CH₂CH₂— pyridin-3-yl 355 pyrazolidin-1-yl —CH₂CH₂— pyridin-3-yl 356 pyrazolin-1-yl —CH₂CH₂— pyridin-3-yl 357 piperidin-1-yl —CH₂CH₂— pyridin-3-yl 358 piperazin-1-yl —CH₂CH₂— pyridin-3-yl 359 4-methylpiperazin-1-yl —CH₂CH₂— pyridin-3-yl 360 morpholin-4-yl —CH₂CH₂— pyridin-3-yl

The compounds which comprise Category II of the present invention can be prepared by the procedure outlined herein below in Scheme IV and Example 4.

Example 4 N-{3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}-benzenesulfonamide (14)

The intermediate, 3-amino-N-phenylbenzenesulfonamide (12), can be conveniently prepared by the following steps from aniline and 3-nitrobenzene-1-sulfonyl chloride. Other sulfonamide intermediates can be prepared in a like manner, the formulator making adjustments to the reaction conditions which are well known to those skilled in the art.

Preparation of 3-nitro-N-phenylbenzenesulfonamide (11): To 3-nitrobenzene-1-sulfonyl chloride (296.9 mg, 1.340 mmol) is added THF (20 mL), aniline (134.8 mg, 1.447 mmol) and potassium carbonate (408.5 mg, 2.955 mmol). The resulting mixture is heated at 50° C. for 16 hours. The reaction mixture is subsequently cooled and concentrated in vacuo after which the residue is treated with 10 ml of H₂O and extracted with EtOAc (75 mL). The organic layer is washed with saturated aqueous NaCl (2×75 mL), dried (MgSO₄), and concentrated in vacuo. The residue is purified over silica (CH₂Cl₂) to afford 257 mg (69% yield) of the desired compound. MS (ESI, pos. ion) m/z: 279 (M+1).

Preparation of 3-amino-N-phenylbenzenesulfonamide (12): To 3-nitro-N-phenylbenzenesulfonamide (255.5 mg, 0.919 mmol) in 4 mL of THF is added SnCl₂ dihydrate (1.015 g, 4.486 mmol). The resulting mixture is heated in a microwave reactor at a power of 75 Watts and 135° C. for 1 min then at 15 Watts and 135° C. for 14 min. The reaction is cooled to room temperature, diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO₃ (10 mL) and allowed to stir for about 12 hours. The reaction mixture is then extracted with EtOAc (75 mL). The organic layer is washed with H₂O (75 mL), saturated aqueous NaCl (2×75 mL), dried (MgSO₄) and concentrated in vacuo to yield a yellow residue. This residue is purified over silica (0-4% MeOH in CH₂Cl₂) to afford 178 mg (78% yield) of the desired compound. ¹H NMR (DMSO-d₆, 300 MHz): δ 5.57 (s, 2H), 6.69 (d, J=8.1 Hz, 1H), 6.84 (d, J=7.5 Hz, 1H), 6.95 (s, 1H), 6.99 (t, J=7.5 Hz, 1H), 7.07 (d, J=8.1 Hz, 2H), 7.12 (t, J=8.1 Hz, 1H), 7.21 (t, J=8.1 Hz, 2H), 10.12 (s, 1H). MS (ESI, pos. ion) m/z: 249 (M+1).

Preparation of 2-chloro-N-(3-morpholinopropyl)pyrimidin-4-amine (13): To 2,4-dichloropyrimidine (5.0 g, 33.5 mmol), diisopropylethylamine (5.85 ml, 33.5 mmol) in 50 mL of a 1:1 mixture of n-BuOH—H₂O (1:1) is added 3-morpholinopropan-1-amine (4.90 mL, 33.5 mmol). The resulting mixture is stirred for 18 hours at room temperature. The mixture is then concentrated in vacuo, diluted with 30 mL H₂O and extracted with EtOAc (3×75 mL). Combined organic layers are washed with saturated aqueous NaHCO₃ (2×75 mL), saturated aqueous NaCl (2×75 mL), and dried (MgSO₄). The residue is purified over silica (25% EtOAc in hexanes) to afford 4.5 g (53% yield) of the desired compound. ¹H NMR (CDCl₃, 300 MHz): δ 1.81 (m, 2H), 2.43-2.62 (m, 6H), 3.30 (m, 2H), 3.79-3.94 (m, 4H), 6.23 (d, J=5.4 Hz, 1H), 6.92 (bs, 1H), 7.99 (bs, 1H). MS (ESI, pos. ion) m/z: 257 (M+1).

Preparation of N-{3-[4-(3-morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}-benzenesulfonamide (14): To 2-chloro-N-(3-morpholinopropyl)pyrimidin-4-amine, 13, (103.1 mg, 0.4016 mmol) in 30 mL of EtOH—H₂O (1:1) is added 3-amino-N-phenylbenzenesulfonamide, 12, (116.5 mg, 0.4697 mmol) and 4 drops concentrated HCl. The resulting mixture is heated at 70° C. with sufficient stirring for 16 hours. The reaction mixture is then cooled to room temperature and concentrated in vacuo. The product is extracted with EtOAc (100 mL). The combined organic layers are washed with H₂O (2×75 mL) and saturated aqueous NaCl (2×75 mL), dried (MgSO₄), and concentrated in vacuo. The resulting residue is purified over silica (5-10% MeOH in CH₂Cl₂) to afford 157 mg (83% yield) of the desired compound. ¹H NMR (DMSO-d₆, 300 MHz): δ 1.72 (m, 2H), 2.34-2.39, (m, 6H), 3.30-3.41 (m, 2H), 3.55-59 (m, 4H), 5.99 (d, J=5.7 Hz, 1H), 7.00 (t, J=7.5 Hz, 1H), 7.11 (d, J=7.5 Hz, 2H), 7.18-7.28 (m, 4H), 7.36 (t, J=7.8 Hz, 1H), 7.81 (bs, 2H), 8.56 (s, 1H), 9.33 (s, 1H), 10.24 (bs, 1H). HRMS calcd for C₂₃H₂₈N₆O₃, 469.2022 m/z (M+H)⁺; observed 469.2020 m/z.

The following are non-limiting examples of compounds which comprise Category II of the present invention, the characterization of which will assist the formulator in establishing the chemical formulae of compounds which are not specifically exemplified herein. Alternatively, these compounds may also be synthesized by the synthetic route or methods described earlier in Scheme I.

N²-[3-(1H-Imidazol-1-ylmethyl)-phenyl]-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine: ¹H NMR (CDCl₃, 300 MHz) δ 1.84 (q, J=6.3 Hz, 2H), 2.27-2.37 (m, 2H), 2.48-2.56 (m, 4H), 3.36-3.44 (m, 2H), 3.77 (t, J=4.5 Hz, 4H), 5.14 (s, 2H), 5.86 (d, J=6.0 Hz, 1H), 6.27 (bs, 1H), 6.80 (d, J=7.5 Hz, 1H), 6.96 (s, 1H), 7.11 (s, 1H), 7.24-7.31 (m, 2H), 7.45 (d, J=7.8 Hz, 1H), 7.60 (d, J=5.4 Hz, 2H), 7.90 (d, J=5.7 Hz, 1H); HRMS calcd for C₂₁H₂₇N₇O, 394.2355 m/z (M+H)⁺; observed 394.2371 m/z.

3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-N-(pyridin-3-ylmethyl)-benzenesulfonamide. ¹H NMR (DMSO-d₆, 300 MHz): δ 1.62-1.77 (m, 2H), 2.28-2.40 (m, 6H), 3.35-3.42 (m, 2H), 3.52-3.57 (m, 4H), 4.05 (d, J=5.4 Hz, 2H), 6.00 (d, J=5.4 Hz, 1H), 7.28-7.34 (m, 3H), 7.42 (t, J=7.8 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.75-7.95 (m, 2H), 8.15 (t, J=6.0 Hz, 1H), 8.44 (d, J=6.0 Hz, 1H), 8.45 (s, 1H), 8.59 (s, 1H), 9.33 (s, 1H). HRMS calcd for C₂₃H₂₉N₇O₃S, 484.2131 m/z (M+H)⁺; observed 484.2148 m/z.

N²-[3-(1H-Indol-2-ylmethyl)-phenyl]-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine.

3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-benzenesulfonamide ¹H NMR (DMSO-d₆, 300 MHz) δ 2.01-2.12 (m, 2H), 2.96-3.12 (m, 2H), 3.14-3.19 (m, 2H), 3.36-3.43 (m, 2H), 3.48-3.56 (m, 2H), 3.79-4.10 (m, 4H), 6.32 (d, J=7.2 Hz, 1H), 7.49 (s, 2H), 7.58-7.65 (m, 3H), 7.92 (d, J=7.2 Hz, 1H), 8.49 (s, 1H), 9.34 (bs, 1H), 11.01 (s, 1H); HRMS calcd for C₁₇H₂₄N₆O₃S, 393.1709 m/z (M+H)⁺; observed 393.1719 m/z. N-(3-Chlorophenyl)-3-[4-(3-pyrrolidin-1-yl-propylamino)-pyrimidin-2-ylamino]-benzamide: HRMS calcd for C₂₄H₂₇N₆OCl, 451.2013 m/z (M+H)⁺; observed 451.2016 m/z.

N-{3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}-benzamide ¹H NMR (DMSO-d₆, 300 MHz): 1.67 (m, 2H), 2.18-2.34 (m, 6H), 3.29-3.42 (m, 2H), 3.53 (t, J=4.5 Hz, 4H), 5.93 (d, J=5.7 Hz, 1H), 7.08-7.25 (m, 3H), 7.45 (bs, 1H), 7.50-7.59 (m, 3H), 7.74-7.85 (m, 1H), 7.96 (d, J=6.9 Hz, 2H), 8.29 (bs, 1H), 8.96 (s, 1H), 10.15 (s, 1H). HRMS calcd for C₂₄H₂₈N₆O₂, 433.2352 m/z (M+H)⁺; observed 433.2357 m/z.

N-Isopropyl-3-[4-(3-pyrrolidin-1-yl-propylamino)-pyrimidin-2-ylamino]-benzamide: HRMS calcd for C₂₁H₃₀N₆O, 383.2559 m/z (M+H)⁺; observed 383.2564 m/z.

N²-[3-(4-Methyl-piperazine-1-sulfonyl)phenyl]-N⁴-(3-morpholin-4-ylpropyl)-pyrimidine-2,4-diamine. ¹H NMR (DMSO-d₆, 300 MHz): δ 1.67-1.78 (m, 2H), 2.15 (s, 3H), 2.28-2.45 (m, 10H), 2.85-2.98 (m, 4H), 3.32-3.47 (m, 2H), 3.58 (t, J=4.5 Hz, 4H), 6.08 (d, J=5.7 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 7.30 (s, 1H), 7.49 (t, J=8.1 Hz, 1H), 7.83 (d, J=5.7 Hz, 1H), 7.92 (bs, 1H), 8.53 (s, 1H), 9.40 (s, 1H). HRMS calcd for, C₂₂H₃₃N₇O₃S 476.2444 m/z (M+H)⁺; observed 476.2449 m/z.

N-{3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}-nicotinamide. ¹H NMR (DMSO-d₆, 300 MHz): δ 1.62-1.73 (m, 2H), 2.20-2.33 (m, 6H), 3.29-3.40 (m, 2H), 3.53 (t, J=4.5 Hz, 4H), 5.93 (d, J=6.0 Hz, 1H), 7.08-7.24 (m, 3H), 7.46 (bs, 1H), 7.56 (dd, J=4.8, 8.1 Hz, 1H), 7.80 (d, J=6.0 Hz, 1H), 8.29 (d, J=8.1 Hz, 2H), 8.76 (d, J=4.8 Hz, 1H), 8.99 (s, 1H), 9.10 (s, 1H), 10.35 (s, 1H). HRMS calcd for C₂₃H₂₇N₇O₂, 434.2304 m/z (M+H)⁺; observed 434.2300 m/z.

N-(3-Chloro-phenyl)-3-[4-(3-pyrrolidin-1-yl-propylamino)-pyrimidin-2-ylamino]-benzamide: HRMS calcd for C₂₄H₂₈N₆OCl, 451.2013 m/z (M+H)⁺; observed 451.2016 m/z.

N-Benzyl-3-[4-(3-pyrrolidin-1-yl-propylamino)-pyrimidin-2-ylamino]-benzamide: HRMS calcd for C₂₅H₃₁N₆O, 431.2559 m/z (M+H)⁺; observed 431.2561 m/z.

4-Dimethylamino-N-{3-[4-(3-morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}-benzamide: HRMS calcd for C₂₆H₃₄N₇O₂, 476.2774 m/z (M+H)⁺; observed 476.2787 m/z.

[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-N-phenylbenzenesulfonamide: HRMS calcd for C₂₃H₂₉N₆O₃S, 469.2022 m/z (M+H)⁺; observed 469.2020 m/z.

3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-N-(2-pyridin-3-yl-ethyl)-benzenesulfonamide: HRMS calcd for C₂₄H₃₂N₇O₃S, 498.2287 m/z (M+H)⁺; observed 498.2300 m/z.

N-{3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}-isonicotinamide: HRMS calcd for C₂₃H₂₈N₇O₂, 434.2304 m/z (M+H)⁺; observed 434.2317 m/z.

N²-[3-(Morpholine-4-sulfonyl)-phenyl]-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine: HRMS calcd for C₂₁H₃₁N₆O₄S, 463.2128 m/z (M+H)⁺; observed 463.2135 m/z.

The compounds which comprise Category III of the present invention are 2,4-di-aminopyrimidines having the formula:

wherein R is a heterocyclic unit chosen from:

wherein R², R³, and R¹⁰ are each defined herein above. The first aspect of Category III relates to R¹ units which are phenyl units substituted by one or more R⁵ units chosen from:

-   -   ii) halogen; —F, —Cl, —Br, and —I;     -   iii) nitro; —NO₂;     -   iv) hydroxy; —OH;     -   v) amino or mono- or di-substituted (C₁-C₄ linear or branched         alkyl)amino; inter alia, —NH₂, —NH(CH₃), and —N(CH₃)₂,     -   vi) substituted or unsubstituted C₁-C₄ linear or branched alkyl;     -   vii) substituted or unsubstituted C₁-C₄ linear or branched         alkoxy;         which are further exemplified herein below in Table V and in the         following examples.

TABLE V No. L R R⁵ 361 —CH₂— piperidine-2-yl 3-chloro 362 —CH₂— N-methylpiperidine-2-yl 3-chloro 363 —CH₂— piperidine-3-yl 3-chloro 364 —CH₂— N-methylpiperidine-3-yl 3-chloro 365 —CH₂— piperidine-4-yl 3-chloro 366 —CH₂— N-methylpiperidine-4-yl 3-chloro 367 —CH₂— pyrrolidin-2-yl 3-chloro 368 —CH₂— N-methylpyrrolidin-2-yl 3-chloro 369 —CH₂— pyrrolidin-3-yl 3-chloro 370 —CH₂— N-methylpyrrolidin-3-yl 3-chloro 371 —CH₂— morpholin-2-yl 3-chloro 372 —CH₂— morpholin-3-yl 3-chloro 373 —CH₂CH₂— piperidine-2-yl 3-chloro 374 —CH₂CH₂— N-methylpiperidine-2-yl 3-chloro 375 —CH₂CH₂— piperidine-3-yl 3-chloro 376 —CH₂CH₂— N-methylpiperidine-3-yl 3-chloro 377 —CH₂CH₂— piperidine-4-yl 3-chloro 378 —CH₂CH₂— N-methylpiperidine-4-yl 3-chloro 379 —CH₂CH₂— pyrrolidin-2-yl 3-chloro 380 —CH₂CH₂— N-methylpyrrolidin-2-yl 3-chloro 381 —CH₂CH₂— pyrrolidin-3-yl 3-chloro 382 —CH₂CH₂— N-methylpyrrolidin-3-yl 3-chloro 383 —CH₂CH₂— morpholin-2-yl 3-chloro 384 —CH₂CH₂— morpholin-3-yl 3-chloro 385 —CH₂— piperidine-2-yl 3-fluoro 386 —CH₂— N-methylpiperidine-2-yl 3-fluoro 387 —CH₂— piperidine-3-yl 3-fluoro 388 —CH₂— N-methylpiperidine-3-yl 3-fluoro 389 —CH₂— piperidine-4-yl 3-fluoro 390 —CH₂— N-methylpiperidine-4-yl 3-fluoro 391 —CH₂— pyrrolidin-2-yl 3-fluoro 392 —CH₂— N-methylpyrrolidin-2-yl 3-fluoro 393 —CH₂— pyrrolidin-3-yl 3-fluoro 394 —CH₂— N-methylpyrrolidin-3-yl 3-fluoro 395 —CH₂— morpholin-2-yl 3-fluoro 396 —CH₂— morpholin-3-yl 3-fluoro 397 —CH₂CH₂— piperidine-2-yl 3-fluoro 398 —CH₂CH₂— N-methylpiperidine-2-yl 3-fluoro 399 —CH₂CH₂— piperidine-3-yl 3-fluoro 400 —CH₂CH₂— N-methylpiperidine-3-yl 3-fluoro 401 —CH₂CH₂— piperidine-4-yl 3-fluoro 402 —CH₂CH₂— N-methylpiperidine-4-yl 3-fluoro 403 —CH₂CH₂— pyrrolidin-2-yl 3-fluoro 404 —CH₂CH₂— N-methylpyrrolidin-2-yl 3-fluoro 405 —CH₂CH₂— pyrrolidin-3-yl 3-fluoro 406 —CH₂CH₂— N-methylpyrrolidin-3-yl 3-fluoro 407 —CH₂CH₂— morpholin-2-yl 3-fluoro 408 —CH₂CH₂— morpholin-3-yl 3-fluoro 409 —CH₂— piperidine-2-yl 3-methyl 410 —CH₂— N-methylpiperidine-2-yl 3-methyl 411 —CH₂— piperidine-3-yl 3-methyl 412 —CH₂— N-methylpiperidine-3-yl 3-methyl 413 —CH₂— piperidine-4-yl 3-methyl 414 —CH₂— N-methylpiperidine-4-yl 3-methyl 415 —CH₂— pyrrolidin-2-yl 3-methyl 416 —CH₂— N-methylpyrrolidin-2-yl 3-methyl 417 —CH₂— pyrrolidin-3-yl 3-methyl 418 —CH₂— N-methylpyrrolidin-3-yl 3-methyl 419 —CH₂— morpholin-2-yl 3-methyl 420 —CH₂— morpholin-3-yl 3-methyl 421 —CH₂CH₂— piperidine-2-yl 3-methyl 422 —CH₂CH₂— N-methylpiperidine-2-yl 3-methyl 423 —CH₂CH₂— piperidine-3-yl 3-methyl 424 —CH₂CH₂— N-methylpiperidine-3-yl 3-methyl 425 —CH₂CH₂— piperidine-4-yl 3-methyl 426 —CH₂CH₂— N-methylpiperidine-4-yl 3-methyl 427 —CH₂CH₂— pyrrolidin-2-yl 3-methyl 428 —CH₂CH₂— N-methylpyrrolidin-2-yl 3-methyl 429 —CH₂CH₂— pyrrolidin-3-yl 3-methyl 430 —CH₂CH₂— N-methylpyrrolidin-3-yl 3-methyl 431 —CH₂CH₂— morpholin-2-yl 3-methyl 432 —CH₂CH₂— morpholin-3-yl 3-methyl 433 —CH₂— piperidine-2-yl 3-methoxy 434 —CH₂— N-methylpiperidine-2-yl 3-methoxy 435 —CH₂— piperidine-3-yl 3-methoxy 436 —CH₂— N-methylpiperidine-3-yl 3-methoxy 437 —CH₂— piperidine-4-yl 3-methoxy 438 —CH₂— N-methylpiperidine-4-yl 3-methoxy 439 —CH₂— pyrrolidin-2-yl 3-methoxy 440 —CH₂— N-methylpyrrolidin-2-yl 3-methoxy 441 —CH₂— pyrrolidin-3-yl 3-methoxy 442 —CH₂— N-methylpyrrolidin-3-yl 3-methoxy 443 —CH₂— morpholin-2-yl 3-methoxy 444 —CH₂— morpholin-3-yl 3-methoxy 445 —CH₂CH₂— piperidine-2-yl 3-methoxy 446 —CH₂CH₂— N-methylpiperidine-2-yl 3-methoxy 447 —CH₂CH₂— piperidine-3-yl 3-methoxy 448 —CH₂CH₂— N-methylpiperidine-3-yl 3-methoxy 449 —CH₂CH₂— piperidine-4-yl 3-methoxy 450 —CH₂CH₂— N-methylpiperidine-4-yl 3-methoxy 451 —CH₂CH₂— pyrrolidin-2-yl 3-methoxy 452 —CH₂CH₂— N-methylpyrrolidin-2-yl 3-methoxy 453 —CH₂CH₂— pyrrolidin-3-yl 3-methoxy 454 —CH₂CH₂— N-methylpyrrolidin-3-yl 3-methoxy 455 —CH₂CH₂— morpholin-2-yl 3-methoxy 456 —CH₂CH₂— morpholin-3-yl 3-methoxy

The compounds which comprise the first aspect of Category III of the present invention can be prepared by the procedure outlined herein below in Scheme V and Example 5.

Example 5 N²-(3-Chlorophenyl)-N⁴-piperidin-2-ylmethyl-pyrimidine-2,4-diamine (16)

Preparation of 2-{[2-(3-chlorophenylamino)pyrimidin-4-ylamino]methyl}-piperidine-1-carboxylic acid tert-butyl ester (15): To a solution of 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (300 mg, 1.25 mmol) and tert-butyl 2-(aminomethyl)-piperidine-1-carboxylate (540 mg, 2.50 mmol) in THF (10 mL) is added diisopropylethyl-amine (0.43 mL, 2.50 mmol). The reaction is heated at reflux for 18 hours and then cooled to room temperature. The crude reaction is partitioned between EtOAc and sat. NaHCO₃. The organic layer is dried (MgSO₄), concentrated in vacuo, and purified over silica (MeOH/CH₂Cl₂) to afford 268 mg (51% yield) of the desired compound: MS (ESI, pos. ion) m/z: 418 (M+1).

Preparation of N²-(3-chlorophenyl)-N⁴-piperidin-2-ylmethyl-pyrimidine-2,4-diamine (16): 2-{[2-(3-chlorophenylamino)pyrimidin-4-ylamino]methyl}-piperidine-1-carboxylic acid tert-butyl ester, 15, is dissolved in neat trifluoroacetic acid (3 mL) and stirred at room temperature for 3 hours. The reaction is concentrated in vacuo and the residue partitioned between EtOAc and sat. NaHCO₃. The organic layer is dried (MgSO₄), concentrated in vacuo, and purified over silica (MeOH/CH₂Cl₂) to afford 7 mg (7% yield) of the desired compound: ¹H NMR (CDCl₃, 300 MHz) δ 1.50-1.63 (m, 1H), 1.70-1.92 (m, 4H), 1.95-2.10 (m, 2H), 2.88 (dt, J=12.0, 3.6 Hz, 1H), 3.30-3.40 (m, 1H), 3.52 (d, J=12.0 Hz, 1H), 3.61-3.70 (m, 1H), 3.87 (d, J=15.3 Hz, 1H) 6.01 (d, J=6.6 Hz, 1H), 7.02 (dt, J=7.5, 1.8 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.25 (t, J=1.8 Hz, 1H), 7.75 (d, J=6.6 Hz, 1H), 7.96 (t, J=1.8 Hz, 1H); HRMS calcd for C₁₆H₂₀ClN₅, 318.1485 m/z (M+H)⁺; observed 318.1481 m/z.

The following are non-limiting examples of compounds which comprise first aspect of Category III of the present invention, the characterization of which will assist the formulator in establishing the chemical formulae of compounds which are not specifically exemplified herein. Alternatively, these compounds may also be synthesized by the synthetic route or methods described earlier in Scheme II.

N²-(3-Chlorophenyl)-N⁴-(1-methylpiperidin-2-ylmethyl)-pyrimidine-2,4-diamine: ¹H NMR (CD₃OD, 300 MHz) δ 1.31-1.50 (m, 2H), 1.60-1.70 (m, 2H), 1.75-1.88 (m, 2H), 2.28-2.40 (m, 2H), 2.47 (s, 3H), 2.96 (dt, J=11.7, 2.7 Hz, 1H), 3.42-3.49 (m, 1H), 3.79 (d, J=12.6 Hz, 1H), 6.03 (d, J=6.3 Hz, 1H), 6.95 (ddd, J=8.1, 1.8, 0.9 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.80 (d, J=5.7 Hz, 1H), 7.88 (t, J=1.8 Hz, 1H); HRMS calcd for C₁₇H₂₂ClN₅, 332.1642 m/z (M+H)⁺; observed 332.1631 m/z.

N²-(3-Chlorophenyl)-N⁴-piperidin-3-ylmethyl-pyrimidine-2,4-diamine: ¹H NMR (CDCl₃, 300 MHz) δ 1.26-1.44 (m, 2H), 1.66-1.80 (m, 1H), 1.95-2.04 (m, 2H), 2.14-2.28 (m, 1H), 2.76 (t, J=12.0 Hz, 1H), 2.90 (dt, J=12.9, 3.3 Hz, 1H), 3.36-3.45 (m, 2H), 3.51 (dd, J=13.8, 6.0 Hz, 1H), 6.14 (d, J=6.6 Hz, 1H), 7.10 (d, J=7.2 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 7.38 (d, J=7.2 Hz, 1H), 7.77 (d, J=6.6 Hz, 1H), 7.98 (s, 1H); HRMS calcd for C₁₆H₂₀ClN₅, 318.1485 m/z (M+H)⁺; observed 318.1483 m/z.

N²-(3-Chlorophenyl)-N⁴-(1-methylpiperidin-3-ylmethyl)-pyrimidine-2,4-diamine: ¹H NMR (CD₃OD, 300 MHz) δ 1.00-1.17 (m, 1H), 1.58-1.73 (m, 1H), 1.78-1.85 (m, 1H), 1.85-2.20 (m, 5H), 2.38 (s, 3H), 2.95 (d, J=11.1 Hz, 1H), 3.08 (d, J=9.9 Hz, 1H), 3.30-3.39 (m, 1H), 6.00 (d, J=5.7 Hz, 1H), 6.95 (ddd, J=7.8, 1.8, 0.9 Hz, 1H), 7.24 (t, J=8.1 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.77 (d, J=6.0 Hz, 1H), 8.09 (s, 1H); HRMS calcd for C₁₇H₂₂ClN₅, 332.1642 m/z (M+H)⁺; observed 332.1637 m/z.

N²-(3-Chlorophenyl)-N⁴-(1-methylpiperidin-4-yl-methyl)-pyrimidine-2,4-diamine hydrochloride salt. ¹H NMR (CD₃OD, 300 MHz): δ 1.53-1.58 (m, 2H), 2.04-2.09 (m, 3H), 2.87 (s, 3H), 2.98-3.05 (m, 2H), 3.46-3.59 (m, 4H), 6.31 (d, 1H, J=7.2 Hz), 7.27-7.48 (m, 3H), 7.25 (d, 1H, J=7.2 Hz), 7.83 (s, 1H). MS (ESI, pos. ion) m/z: 332 (M+1).

N²-(3-Chlorophenyl)-N⁴-[2-(1-methylpyrrolidin-2-yl)-ethyl]-pyrimidine-2,4-diamine: HRMS calcd for C₁₇H₂₂N₅Cl, 332.1642 m/z (M+H)⁺; observed 332.1638 m/z.

N²-(3-Chlorophenyl)-N⁴-morpholin-2-ylmethyl-pyrimidine-2,4-diamine trifluoroacetate salt: ¹H NMR (DMSO-d6, 300 MHz) δ 2.82-2.88 (m, 1H), 2.98-3.03 (m, 1H), 3.14-3.30 (m, 4H), 3.71 (t, J=12.0 Hz, 2H), 3.87-3.93 (m, 1H), 4.01 (d, J=12.3 Hz, 1H), 7.11 (d, J=8.1 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.90 (d, J=6.0 Hz, 1H), 9.33 (s, 3H), 8.58 (bs, 1H), 9.07 (bs, 2H), 10.30 (bs, 1H); HRMS calcd for C₁₅H₁₈N₅ClO, 320.1278 m/z (M+H)⁺; observed 320.1277 m/z.

N²-(3-Chlorophenyl)-N⁴-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-pyrimidine-2,4-diamine ¹H NMR (CDCl₃, 300 MHz) δ 1.63-1.70 (m, 2H), 1.78-1.90 (m, 2H), 1.95-2.08 (m, 2H), 2.11-2.20 (m, 2H), 3.27-3.33 (m, 2H), 4.56-4.63 (m, 1H), 5.85 (d, J=5.7 Hz, 1H), 6.95 (bs, 1H), 6.98 (dd, J=7.5, 0.6 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.35 (dd, J=8.1, 1.2 Hz, 1H), 7.86 (t, J=1.8 Hz, 1H), 7.90 (d, J=5.1 Hz, 1H); HRMS calcd for C₁₈H₂₂N₅Cl, 344.1642 m/z (M+H)⁺; observed 344.1644 m/z.

N²-(3-Chloro-phenyl)-N⁴-(2,2,6,6-tetramethyl-piperidin-4-yl)-pyrimidine-2,4-diamine: (ESI, neg. ion) m/z: 395 (M−1).

N²-(3-Chloro-phenyl)-N⁴-piperidin-4-ylmethyl-pyrimidine-2,4-diamine.

N²-(3-Chloro-phenyl)-N⁴-(1-isopropyl-piperidin-3-ylmethyl)-pyrimidine-2,4-diamine: (ESI, pos. ion) m/z: 360 (M+1).

The second aspect of Category III relates to R units which comprise a chiral carbon atom. Scheme VI herein below and the following examples illustrate this second aspect of Category III of the present invention.

Example 6 N²-(3-Chlorophenyl)-N⁴-{[(2S)-1-methylpyrrolidin-2-yl]methyl}pyrimidine-2,4-diamine (17)

Preparation of tert-butyl (2S)-2-[({2-[(3-chlorophenyl)amino]pyrimidin-4-yl}amino)methyl]pyrrolidine-1-carboxylate (16): To a solution of 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine, 3, (300 mg, 1.25 mmol) and tert-butyl (2S)-2-(aminomethyl)pyrrolidine-1-carboxylate (500 mg, 2.50 mmol) in THF (10 mL) is added diisopropylethylamine (0.43 mL, 2.50 mmol). The reaction was heated at reflux for 18 hours and then cooled to room temperature. The crude reaction is then partitioned between EtOAc and sat. NaHCO₃. The organic layer is dried (MgSO₄), concentrated in vacuo, and purified over silica (MeOH/CH₂Cl₂) to afford 160 mg (32% yield) of the desired product: MS (ESI, pos. ion) m/z: 404 (M+1).

Preparation of N²-(3-chlorophenyl)-N⁴-{[(2S)-1-methylpyrrolidin-2-yl]methyl}pyrimidine-2,4-diamine (17): To a solution of tert-butyl (2S)-2-[({2-[(3-chlorophenyl)amino]pyrimidin-4-yl}amino)methyl]pyrrolidine-1-carboxylate (160 mg, 0.40 mmol) in THF (3 mL) is added lithium aluminum hydride (2 M in THF, 0.6 mL, 1.19 mmol). The reaction is stirred at room temperature for 24 hours and then quenched with NaOH (1 N, 2 mL) and stirred for an additional hour. The reaction solution is partitioned between EtOAc and sat. NaHCO₃. The organic layer is dried (MgSO₄), concentrated in vacuo, and purified over silica (MeOH/CH₂Cl₂) to afford 22 mg (17% yield) of the desired compound: ¹H NMR (CDCl₃, 300 MHz) δ 1.58-1.68 (m, 1H), 1.70-1.83 (m, 2H), 1.99-2.11 (m, 1H), 2.29 (q, J=8.7 Hz, 1H), 2.43 (s, 3H), 2.48-2.58 (m, 1H), 3.04-3.12 (m, 1H), 3.29 (t, J=6.3 Hz, 1H), 3.77 (d, J=11.7 Hz, 1H), 6.01 (d, J=6.0 Hz, 1H), 6.94 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.49 (ddd, J=8.4, 2.1, 0.9 Hz, 1H), 7.78 (d, J=6.0 Hz, 1H), 7.89 (t, J=2.1 Hz, 1H); HRMS calcd for C₁₆H₂₀ClN₅, 318.1485 m/z (M+H)⁺; observed 318.1491 m/z.

The (2R) enantiomer can be prepared in the same manner as described herein above.

Example 7 N²-(3-Chlorophenyl)-N⁴-[(2S)-pyrrolidin-2-ylmethyl]pyrimidine-2,4-diamine (18)

Preparation of N²-(3-chlorophenyl)-N⁴-[(2S)-pyrrolidin-2-ylmethyl]pyrimidine-2,4-diamine (18): To a solution of tert-butyl (2S)-2-[({2-[(3-chlorophenyl)amino]-pyrimidin-4-yl}amino)methyl]pyrrolidine-1-carboxylate, 15, (150 mg, 0.37 mmol) in CH₂Cl₂ (5 mL) is added trifluoroacetic acid (3 mL). The reaction is stirred at room temperature for 24 hours then partitioned between EtOAc and sat. NaHCO₃. The organic layer is dried (MgSO₄), concentrated in vacuo, and purified over silica (MeOH/CH₂Cl₂) to afford 36 mg (32% yield) of the desired material: ¹H NMR (CDCl₃, 300 MHz) δ 1.43-1.56 (m, 1H), 1.70-1.91 (m, 2H), 1.93-2.06 (m, 1H), 2.97 (t, J=6.9 Hz, 2H), 3.16-3.29 (m, 1H), 3.41-3.52 (m, 1H), 3.54-3.66 (m, 1H), 5.71 (t, J=5.1 Hz, 1H), 5.91 (d, J=6.0 Hz, 1H), 6.96 (ddd, J=7.8, 5.7, 0.9 Hz, 1H), 7.20 (t, J=8.1 Hz, 1H), 7.26-7.32 (m, 1H), 7.57 (bs, 1H), 7.91 (d, J=5.7 Hz, 1H), 7.99 (s, 1H); HRMS calcd for C₁₅H₁₈ClN₅, 304.1329 m/z (M+H)⁺; observed 304.1319 m/z.

Example 8

N²-(3-Chlorophenyl)-N⁴-{[(3S)-1-methylpyrrolidin-3-yl]methyl}pyrimidine-2,4-diamine (20)

Preparation of tert-butyl (3S)-3-[({2-[(3-chlorophenyl)amino]pyrimidin-4-yl}amino)methyl]pyrrolidine-1-carboxylate (19): To a solution of 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (500 mg, 2.08 mmol) and tert-butyl (3S)-3-(aminomethyl)pyrrolidine-1-carboxylate (625 mg, 3.12 mmol) in THF (10 mL) is added diisopropylethylamine (0.73 mL, 4.16 mmol). The reaction is heated at reflux for 18 hours and then cooled to room temperature. The crude reaction is partitioned between EtOAc and sat. NaHCO₃. The organic layer is dried (MgSO₄), concentrated in vacuo, and purified over silica (MeOH/CH₂Cl₂) to afford 356 mg (42% yield) of the desired compound: MS (ESI, pos. ion) m/z: 404 (M+1).

Preparation of N²-(3-chlorophenyl)-N⁴-{[(3S)-1-methylpyrrolidin-3-yl]methyl}pyrimidine-2,4-diamine (20): To a solution of tert-butyl (3S)-3-[({2-[(3-chlorophenyl)-amino]pyrimidin-4-yl}amino)methyl]pyrrolidine-1-carboxylate, 19, (356 mg, 0.88 mmol) in THF (2 mL) is added lithium aluminum hydride (2 M in THF, 1.32 mL, 2.64 mmol). The reaction is heated to 50° C. for 3 days, cooled to room temperature, quenched with NaOH (1 N, 2 mL) and stirred for an additional hour. The reaction mixture is extracted with EtOAc (2×25 mL) and the combined organic layers are dried (MgSO₄), concentrated in vacuo, and purified over silica (MeOH/CH₂Cl₂) to afford 190 mg (68% yield) of the desired product: ¹H NMR (DMSO, 300 MHz) δ 1.40-1.50 (m, 1H), 1.86-1.96 (m, 1H), 2.23 (s, 3H), 2.25-2.33 (m, 1H), 2.34-2.41 (m, 1H), 2.42-2.54 (m, 5H), 5.96 (d, J=5.7 Hz, 1H), 6.89 (dt, J=7.5, 0.9 Hz, 1H), 7.22 (t, J=8.4 Hz, 1H), 7.39 (bs, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.74-7.85 (m, 2H), 8.15 (bs, 1H), 9.21 (s, 1H); HRMS calcd for C₁₆H₂₀ClN₅, 318.1485 m/z (M+H)⁺; observed 318.1485 m/z.

In some instances the formulator will find it necessary to synthesize various R units encompassed within the scope of the present invention. Schemes IX and X and Examples 9 and 10 herein below disclose examples of compounds having substituted heterocyclic units for R.

Example 9 1-(4-{3-[2-(3-Chloro-phenylamino)-pyrimidin-4-ylamino]-propyl}-piperazin-1-yl)-ethanone (23)

Preparation of 3-(4-acetylpiperazin-1-yl)propanenitrile (21): To 1-(piperazin-1-yl)ethanone (5 g, 39 mmol) in MeOH (50 mL) at 0° C. is added acrylonitrile (2.57 mL, 39 mmol) in one portion. The resulting reaction is stirred for 12 hours while allowing the reaction to warm to room temperature. The reaction mixture is concentrated in vacuo and the resulting residue diluted with 5 mL of water and extracted with EtOAc (3×25 mL). The combined organic layers are dried (MgSO₄) and concentrated in vacuo. The residue is purified over silica (2% MeOH in CH₂Cl₂) to afford 6.4 g (91% yield) of the desired compound. ¹H NMR (CDCl₃, 300 MHz) δ2.08 (s, 3H), 2.46 (t, J=5.1 Hz, 2H), 2.51-2.53 (m, 4H), 2.71 (t, J=6.9 Hz, 2H), 3.48 (t, J=5.1 Hz, 2H), 3.26 (t, J=5.1 Hz, 2H). MS (ESI, pos. ion) m/z: 182 (M+1).

Preparation of 1-(4-(3-aminopropyl)piperazin-1-yl)ethanone (22): A Parr hydrogenation vessel is charged with ethanol (200 mL) and purged with nitrogen for 10 minutes. Raney nickel catalyst (20 g), 3-(4-acetylpiperazin-1-yl)propanenitrile, 21, (4.12 g, 22.64 mmol) dissolved in ethanol (138 mL), and NH₄OH (98 mL) are added. The flask is then cooled to 0° C. and purged with ammonia gas for 15 minutes. Hydrogen gas is then introduced and the reaction vessel shaken for 18 hours at 40 psi of hydrogen. Once complete, the reaction solution is filtered through celite, and the solute concentrated in vacuo and used without further purification. MS (ESI, pos. ion) m/z: 186 (M+1).

Preparation of 1-(4-{3-[2-(3-chloro-phenylamino)-pyrimidin-4-ylamino]-propyl}-piperazin-1-yl)-ethanone (23): To 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (0.5 g, 2.09 mmol) in THF (13 mL) is added DIPEA (0.73 mL, 4.18 mmol) followed by 1-(4-(3-aminopropyl)-piperazin-1-yl)ethanone, 22, (0.77 g, 4.18 mmol). The resulting mixture is refluxed for 12 hours after which the reaction mixture is cooled to room temperature and the solvent removed in vacuo. To the resulting residue is added water (50 mL) and the solution is washed with EtOAc (3×100 mL). The combined organic layers are dried (MgSO₄) and concentrated in vacuo. The residue which is obtained is purified over silica (10% MeOH in CH₂Cl₂) to afford 0.173 g (10% yield) of the desired compound. ¹H NMR (DMSO-d₆, 300 MHz) δ1.67-1.75 (m, 2H), 1.97 (s, 3H), 2.27-2.40 (m, 6H), 3.37-3.42 (m, 6H), 5.96 (d, J=6.0 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 7.21 (t, J=8.1 Hz, 1H), 7.28 (bs, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.80 (bs, 1H), 8.13 (bs, 1H), 9.19 (s, 1H). MS (ESI, pos. ion) m/z: 389 (M+1). HRMS calcd for C₁₉H₂₅ClN₆O, 389.1857 m/z (M+H)⁺; observed 389.1851 m/z.

Example 10 N²-(3-Chloro-phenyl)-N⁴-[3-(4-methanesulfonyl-piperazin-1-yl)-propyl]-pyrimidine-2,4-diamine (26)

Preparation of 3-(4-(methylsulfonyl)piperazin-1-yl)propanenitrile (24): To 1-(methylsulfonyl)piperazine (1 g, 6.09 mmol) in MeOH (11 mL) at 0° C. is added acrylonitrile (0.402 mL, 6.09 mmol). The reaction mixture is concentrated in vacuo and the resulting residue diluted with 5 mL of water and extracted with EtOAc (3×25 mL). The combined organic layers are dried (MgSO₄) and concentrated in vacuo. The residue is purified over silica (2% MeOH in CH₂Cl₂) to afford 1.1 g (99% yield) of the desired compound. ¹H NMR (CDCl₃, 300 MHz) δ2.56 (t, J=6.9 Hz, 2H), 2.66 (t, J=4.8 Hz, 4H), 2.76 (t, J=6.9 Hz, 2H), 2.81 (s, 3H), 3.30 (t, J=4.8 Hz, 4H). MS (ESI, pos. ion) m/z: 218 (M+1).

Preparation of 3-(4-(methylsulfonyl)piperazin-1-yl)propan-1-amine (25): A Parr hydrogenation vessel is charged with ethanol (200 mL) and purged with nitrogen for 10 minutes. Raney nickel catalyst (4.5 g), 3-(4-(methylsulfonyl)piperazin-1-yl)propanenitrile, 24, (1.1 g, 5.07 mmol) dissolved in ethanol (50 mL), and NH₄OH (98 mL) are added. The flask is then cooled to 0° C. and purged with ammonia gas for 15 minutes. Hydrogen gas is then introduced and the reaction vessel shaken for 18 hours at 40 psi of hydrogen. Once complete, the reaction solution is filtered through celite, and the solute concentrated in vacuo and used without further purification. ¹H NMR (MeOD, 300 MHz) δ 1.70 (m, 2H), 2.48 (t, J=7.2 Hz, 2H), 2.59 (t, J=4.2 Hz, 4H), 2.71 (t, J=6.6 Hz, 2H), 2.86 (s, 3H), 3.25 (t, J=4.8, 4H).

Preparation of N²-(3-Chloro-phenyl)-N⁴-[3-(4-methanesulfonyl-piperazin-1-yl)-propyl]-pyrimidine-2,4-diamine (26): To 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (0.2 g, 0.837 mmol) in THF (10 mL) is added DIPEA (0.29 mL, 1.67 mmol) followed by 3-(4-(methylsulfonyl)piperazin-1-yl)propan-1-amine, 25, (0.0.369 g, 1.67 mmol). The resulting mixture is refluxed for 12 hours after which the reaction mixture is cooled to room temperature and the solvent removed in vacuo. To the resulting residue is added water (50 mL) and the solution is washed with EtOAc (3×100 mL). The combined organic layers are dried (MgSO₄) and concentrated in vacuo. The residue which is obtained is purified over silica (10% MeOH in CH₂Cl₂) to afford 0.129 g (50% yield) of the desired compound. ¹H NMR (DMSO-d₆, 300 MHz) δ1.71 (m, 2H), 2.39-2.45 (m, 6H), 2.84 (s, 3H), 3.08 (m, 4H), 3.38 (m, 2H), 5.96 (d, J=5.7 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 7.18-7.27 (m, 2H), 7.58 (d, J=7.5 Hz, 1H), 7.81 (bs, 1H), 8.12 (bs, 1H), 9.18 (s, 1H). MS (ESI, pos. ion) m/z: 425 (M+1). HRMS calcd for C₁₈H₂₅ClN₆O₂S, 425.1526 m/z (M+H)⁺; observed 425.1512 m/z.

The compounds of the present invention are inhibitors of Protein Kinase C-alpha (PKC-α), therefore, they are PKC-α inhibitors which are capable of improving myocardial contraction and relaxation performance and slow the progression of heart failure. Certain exemplified compounds may also potentially inhibit additional isoforms of conventional PKC, such as PKC-β or PKC-γ. This is not undesirable and can lead to increased pharmacological effects.

The level of disease, for example, the relative degree of heart failure due to PKC-α activity will vary from patient to patient and be predicated by other exacerbating circumstances, inter alia, presence of other disease conditions (diabetes, high blood pressure, and the like) or patients may suffer from other conditions such as obesity. Therefore, the formulator may be required to employ differing levels or amounts of the compounds described herein to obtain a therapeutic level. The formulator can determine this amount by any of the known testing procedures known to the artisan.

Formulations

The present invention also relates to compositions or formulations which comprise the PKC-α inhibitors according to the present invention. In general, the compositions of the present invention comprise:

-   -   a) an effective amount of one or more         2-arylamino-4-(heterocyclic)aminopyrimidines or salts thereof         according to the present invention which are effective for         inhibiting PKC-α; and     -   b) one or more excipients.

For the purposes of the present invention the term “excipient” and “carrier” are used interchangeably throughout the description of the present invention. One aspect of excipient and carrier relate to their definition in terms of a medicament, said terms are defined in that respect as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”

The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.

Non-limiting examples of compositions according to the present invention include:

-   -   a) from about 0.001 mg to about 1000 mg of one or more PKC-α         inhibitors according to the present invention; and     -   b) one or more excipient.

Another embodiment according to the present invention relates to the following compositions:

-   -   a) from about 0.01 mg to about 100 mg of one or more PKC-α         inhibitors according to the present invention; and     -   b) one or more excipient.

A further embodiment according to the present invention relates to the following compositions:

-   -   a) from about 0.1 mg to about 10 mg of one or more PKC-α         inhibitors according to the present invention; and     -   b) one or more excipient.

The term “effective amount” as used herein means “an amount of one or more PKC-α inhibitors, effective at dosages and for periods of time necessary to achieve the desired result.” An effective amount may vary according to factors known in the art, such as the disease state, age, sex, and weight of the human or animal being treated. Although particular dosage regimes may be described in examples herein, a person skilled in the art would appreciated that the dosage regime may be altered to provide optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. In addition, the compositions of the present invention can be administered as frequently as necessary to achieve a therapeutic amount.

Method of Use

The present invention also relates to a method for improving cardiac contraction/relaxation parameters in heart failure patients and/or attenuating adverse cardiac remodeling and prevent or slow the progression of worsening heart failure. The present method comprises the step of administering to a human or higher mammal an effective amount of a composition comprising one or more of the PKC-α inhibitors according to the present invention.

The present method comprised a method for treating or preventing a disease or medical condition selected from diabetes, numerous forms of cancer, microalbinuria, endothelial dysfunction, cerebrovascular disease, stroke, coronary heart disease, cardiovascular disease and sequela (e.g. arrhythmia, sudden death, increased infarct size, congestive heart failure, angina), myocardial ischemic states, hypertension, lipid disorders, ischemia-reperfusion injury, atherosclerosis, peripheral artery/vascular disease, microvascular complications of diabetes (neuropathy, nephropathy, retinopathy), restenosis, renal disease, blood coagulation disorders, inflammatory diseases, cardiac hypertrophy, dilated cardiomyopathy, ischemic injury and suboptimal mitogen stimulation said method comprised of the steps of administering to a patient in need thereof a therapeutic amount of a PKC-α inhibitor as disclosed herein.

The present invention also relates to the use of the 2-arylamino-4-(heterocyclic)-amino-pyrimidines or salts thereof, according to the present invention in the manufacture of a medicament for the treatment of heart disease wherein inhibition of PKC-α provides a benefit.

Procedures Assessment of PKC-α Inhibitory Activity

Measurement of PKCα enzyme activity is performed using full-length human PKCα enzyme (Upstate Biotechnology) at a final concentration of 0.12 μg/ml in a kinase assay buffer (0.09 mg/ml bovine serum albumin (BSA), 210 μM ethylenediaminetetraacetic acid (EDTA), 360 μM CaCl₂, 1 mM Tris-HCl, pH=7.5, 0.5 mM MgCl₂, 0.015 mg/ml phosphatidylserine and 0.015 mg/ml diacylglycerol). The reaction is initiated by addition of adenosine triphosphate (ATP; final concentration 45 μM) and a peptide substrate consisting of amino acids 28-43 (Ala-Ala-Lys-Ile-Gln-Ala-Ser-Phe-Arg-Gly-His-Met-Ala-Arg-Lys-Lys) of neurogranin (Promega; final concentration 22 μM). After a 30 minute incubation at 24° C. the reaction is terminated by adding 5 μL of the reaction mixture into 50 μL of MALDI matrix solution (5 mg/ml α-cyano-4-hydroxycinnamic acid in 50% Acetonitrile/H₂O, 0.1% TFA, 5 mM ammonium phosphate). Two microliters of the stopped reaction mixture is transferred onto a MALDI-TOF mass spectrometer target plate.

All spectra are collected on an Applied Biosystems 4700 Proteomics Analyzer MALDI-TOF MS equipped with a Nd:YAG laser (355 nm, 3 ns pulse width, 200 Hz repetition rate) in negative ion reflector mode. The system is operated with 4700 Explorer software, version 3.0. Automated acquisition parameters are adjusted to capture and average only those individual spectra within defined success criteria. Specifically, signal intensities for the substrate peptide are set to a minimum threshold of 3000 counts and a maximum intensity of 65,000 counts. This ensured that neither null spectra nor saturated spectra are averaged into the final readout. Between 1000 and 1500 laser shots are averaged for each sample. Data are collected in triplicate from 3 successive days to capture the maximum variability related to preparation of enzyme reaction, transfer of samples to MALDI target plates, data collection, and data extraction.

The isotope cluster areas for each peptide substrate and product peaks are extracted into a Microsoft Excel worksheet from the 10×10 array of spectral data simultaneously using the automated analysis function provided within the 4700 Explore software. The isotope cluster area is defined by the software algorithm based on the molecular weight and the general elemental composition of the peptides. The percent conversion (% C) of substrate to product is calculated as the cluster area of the product (P) divided by the sum of the cluster areas of the substrate (S) and the product multiplied by 100 as represented by the following equation:

${\% \mspace{14mu} C} = {\frac{P}{P + S} \times 100.}$

For dose-dependent inhibition studies, the inhibition is plotted as a % Maximal Activity (% MA). Equation one is a measure of the ratio of product to substrate then solving for the % C. However, to measure inhibition of the enzyme activity, one must measure the degree to which that activity (% C) is curtailed. Thus the dose-dependant inhibition data is plotted as % MA where the maximal activity is the % C measured in control reactions with no inhibitor as represented by the following equation:

${\% \mspace{14mu} {MA}} = {\frac{\% \mspace{14mu} C\mspace{14mu} {with}\mspace{14mu} {inhibitor}}{\% \mspace{14mu} C\mspace{14mu} {with}\mspace{14mu} {no}\mspace{14mu} {inhibitor}} \times 100.}$

Evaluation of PKCα Inhibitors in Cardiomyocytes

Determination of PKCα activity in cells is determined using murine HL-1 atrial cardiac muscle cells. On day 1, HL-1 cells are plated at 18,000 cells/well in a 96-well tissue culture plate. Cells are cultured in 0.1 ml Claycomb growth medium (without norepinephrine) supplemented with 10% fetal bovine serum, 200 mM glutamine and 1% antibiotic/antimycotic. On day 2, cells are washed 1× with 100 μl of phosphate buffered saline (PBS) and the medium is replaced with 100 μl serum free Claycomb medium supplemented with 200 mM glutamine. For compound testing, the medium is removed and replaced with serum free Claycomb medium supplemented with 200 mM glutamine containing different concentrations of compound at a final volume of 50 μl. Compounds are dissolved in 100% dimethylsulfoxide (DMSO) and final DMSO concentrations are maintained at 0.5%. Plates are then incubated for 30 minutes at 37° C. in a 5% CO₂ incubator. The medium is then removed and the plates are rinsed 1× with ice-cold 100 μl PBS. The PBS is removed and replaced with 10 μl of ice-cold lysis buffer consisting of B-PERII detergent (Pierce) diluted 1:1 in distilled water and including a final concentration of 0.3% β-mercaptoethanol, 50 μg/ml phenylmethylsulfonylfluoride (PMSF) 10 mM benzamidine, 10 nM okadaic acid, 20 μg/ml leupeptin and 20 μg/ml soybean trypsin inhibitor. The plates are gently mixed for 10-20 minutes at 4° C. Next, 90 μl of coactivation buffer, consisting of 0.1 mg/ml BSA, 250 μM EDTA, 400 μM CaCl₂, is added to each well. Twenty-five microliters of the cell lysate/coactivation buffer solution is removed from each well and the enzyme activity measured by addition of 25 μl of substrate solution, consisting of 0.1 mg/ml bovine serum albumin, 235 μM EDTA, 400 μM CaCl₂, 1 mM Tris-HCl, pH=7.5, 0.5 mM MgCl₂, 0.015 mg/ml phosphatidylserine and 0.015 mg/ml diacylglycerol, 20 μM ATP and 2 μM of an octapeptide fragment of the EGF receptor (Arg-Lys-Arg-Thr-Leu-Arg-Arg-Leu). After a 30 minute incubation at 24° C. the reaction is terminated by adding 5 μL of the reaction mixture into 50 μL of MALDI matrix solution (5 mg/ml α-cyano-4-hydroxycinnamic acid in 50% Acetonitrile/H₂O, 0.1% TFA, 5 mM ammonium phosphate). Two microliters of the stopped reaction mixture is transferred onto a MALDI-TOF mass spectrometer target plate. Dose-dependent inhibition is measured by mass spectrometry as % maximal activity as described above for the isolated PKCα inhibition assays.

In Vivo Evaluation of PKCα Inhibitors in the Anesthetized Rat

Selected PKCα inhibitors are evaluated in rats with acute heart failure (HF) after myocardial infarction (MI) for effects on cardiac contractility and hemodynamics. Male, Sprague-Dawley rats are anesthetized with isoflurane, intubated, placed on ventilators and maintained at a surgical plane of anesthesia during the course of the experiment. The animals are instrumented, for the measurement of left ventricular function (+dP/dt, LVDP), arterial blood pressure, and the ECG is monitored for the incidence of arrhythmias. A thoracotomy is performed at the fourth intercostal space to visualize the heart, the pericardium is opened and a suture is placed around the left anterior descending (LAD) coronary artery approximately 3-4 mm from its origin. When hemodynamic values are stabilized, the LAD is permanently ligated to induce a myocardial infarction. Severe arrhythmia are treated with the administration of lidocaine. Typically, cardiac function stabilized approximately 40-60 min after ligation and baseline hemodynamic values are measured. N²-(3-chlorophenyl)-N⁴-(3-(dimethylamino)propyl)pyrimidine-2,4-diamine, 100 and 300 nmol/kg/min for 10 min each dose, and hemodynamic parameters are measured after each dose. The effects of treatment are normalized to pre-treatment baseline values and expressed as a percentage. Statistical significance (p<0.05) is evaluated using one-way ANOVA and Dunnett's multiple comparison test.

In Vivo Evaluation of PKCα Inhibitors in the Anesthetized Rat

Selected PKCα inhibitors are evaluated in rats with myocardial infarction (MI) for effects on cardiac contractility and hemodynamics.

Male, Sprague-Dawley or Lewis rats weighing between 225-500 gm are anesthetized with isoflurane and an MI is induced as follows. A thoracotomy is performed at the fourth intercostal space to visualize the heart, the pericardium is opened and a suture is placed around the left anterior descending (LAD) coronary artery approximately 3-4 mm from its origin. When hemodynamic values are stabilized, the LAD is permanently ligated to induce a myocardial infarction. Severe arrhythmias are treated with the administration of lidocaine. Typically, cardiac function stabilized approximately 40-60 min after ligation and baseline hemodynamic values are measured.

The effects of inhibitors on cardiac contractility and hemodynamics are evaluated in MI rats as follows. The animals are anesthetized with isoflurane. A femoral artery is isolated and cannulated for the measurement of systemic blood pressure. A jugular vein is isolated and cannulated for the intravenous infusion of inhibitor. The right carotid artery is isolated and a Millar conductance catheter is inserted to the left ventricle (LV) of the heart. The LV systolic pressure, end-diastolic pressure, +dP/dt_(max), −dP/dt_(min), and heart rate are derived from the LV pressure waveform. Mean arterial blood pressure is derived from the systemic blood pressure waveform. Data are recorded continuously and derived using computerized data acquisition software (Notocord or Powerlab).

After a period of stabilization, PKC-α inhibitors are infused at the following infusion doses in MI rats: 10, 30, 100, 300 and 1000 nmol/kg/min. The infusion of each dose is allowed to run for at least five minutes. At the end of the test infusions, 5.0 μg/kg/min of dobutamine is infused. The effects of treatment are normalized to pretreatment baseline values and expressed as a percentage. Statistical significance (p<0.05) is evaluated using a one-way ANOVA and Dunnett's multiple comparison test.

Table VI provides non-limiting examples of PKC-α IC₅₀ values for representative compounds of the present invention.

TABLE VI PKC-α Compound IC₅₀ (nM) N²-(3-Chlorophenyl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine 2 N²-(3-Chlorophenyl)-N⁴-[3-(4-methylpiperazin-1-yl)-propyl]-pyrimidine- 5 2,4-diamine 1-{3-[2-(3-Chlorophenylamino)-pyrimidin-4-ylamino]-propyl}-pyrrolidin- 710 2-one N²-[3-Trifluoromethyl-phenyl]-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine- 0.5 2,4-diamine N⁴-(3-Pyrrolidin-1-yl-propyl)-N²-[3-methylphenyl]-pyrimidine-2,4-diamine 40 N⁴-(3-Pyrrolidin-1-yl-propyl)-N²-[3-methoxyphenyl]-pyrimidine-2,4- 16 diamine N²-(3-Chlorophenyl)-N⁴-[2-(1-methylpyrrolidin-2-yl)-ethyl]-pyrimidine- 0.4 2,4-diamine N²-(3-Chlorophenyl)-N⁴-morpholin-2-ylmethyl-pyrimidine-2,4-diamine 23 N²-(3-Chlorophenyl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine 3 N²-(3-Chlorophenyl)-N⁴-(1-methylpiperidin-4-ylmethyl)-pyrimidine-2,4- 30 diamine N²-(3-Chlorophenyl)-N⁴-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-pyrimidine- 4 2,4-diamine N²-(4-(Benzyloxy)-3-chlorophenyl)-N⁴-(3-pyrrolidin-1-yl-propyl)- 40 pyrimidine-2,4-diamine N²-(3-Nitrophenyl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine 1 N²-(3-Nitrophenyl)-N⁴-(3-pyrrolidin-1-yl-propyl)-pyrimidine-2,4-diamine 2 N²-(3-Bromophenyl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine 1 N²-(3-Isopropylphenyl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4- 80 diamine N²-Biphenyl-3-yl-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine 3 N²-(3,5-Bis-trifluoromethyl-phenyl)-N⁴-(3-morpholin-4-yl-propyl)- 21 pyrimidine-2,4-diamine N²-[3-(Pyridin-3-yl)-phenyl]-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4- 28 diamine N-{3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}- 23 benzenesulfonamide N²-[3-(N,N-dimethylamino)-phenyl]-N⁴-(3-morpholin-4-yl-propyl)- 53 pyrimidine-2,4-diamine N²-(3-Fluorophenyl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4-diamine 64 N²-(3-Nitro-biphenyl-3-yl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4- 182 diamine 3-[4-(3-Morpholin-4-ylpropylamino)-pyrimidin-2-ylamino]-N-(pyridin-3- 52 ylmethyl)-benzenesulfonamide N²-[3-(1H-Indol-2-ylmethyl)-phenyl]-N⁴-(3-morpholin-4-yl-propyl)- 18 pyrimidine-2,4-diamine {3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}- 465 methanol N²-(3-(Benzo[d]thiazol-2-yl)-phenyl)-N⁴-(3-morpholin-4-yl-propyl)- 40 pyrimidine-2,4-diamine 3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]- 14 benzenesulfonamide N-(3-Chlorophenyl)-3-[4-(3-pyrrolidin-1-yl-propylamino)-pyrimidin-2- 12 ylamino]-benzamide N-{3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}- 25 benzamide N-Isopropyl-3-[4-(3-Pyrrolidin-1-yl-propylamino)-pyrimidin-2-ylamino]- 344 benzamide N²-(3-Phenoxyphenyl)-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine-2,4- 50 diamine N²-(3-Chlorophenyl)-N⁴-piperidin-4-ylmethyl- 37 pyrimidine-2,4-diamine N²-(3-Chlorophenyl)-N⁴-(1-methylpiperidin-3-ylmethyl)- 4 pyrimidine-2,4-diamine N²-(3-Chlorophenyl)-N⁴-piperidin-3-ylmethyl- 25 pyrimidine-2,4-diamine N²-(3-Chlorophenyl)-N⁴—[(3S)-1-methylpyrrolidin-3-ylmethyl]- 13 pyrimidine-2,4-diamine N²-(3-Chlorophenyl)-N⁴—[(3R)-1-methylpyrrolidin-3-ylmethyl]- 7 pyrimidine-2,4-diamine N²-[3-(4-Methyl-piperazine-1-sulfonyl)phenyl]-N⁴-(3-morpholin-4- 83 ylpropyl)-pyrimidine-2,4-diamine N-{3-[4-(3-Morpholin-4-yl-propylamino)-pyrimidin-2-ylamino]-phenyl}- 112 nicotinamide N²-[3-(1H-Indol-4-yl)-phenyl]-N⁴-(3-morpholin-4-yl-propyl)-pyrimidine- 12 2,4-diamine

While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention. 

1. A compound having the formula:

wherein R is a substituted or unsubstituted heterocyclic unit containing from 3 to 7 atoms; L is a linking group having the formula: —[C(R^(4a)R^(4b))]_(n)— each R^(4a) and R^(4b) is independently chosen from: i) hydrogen; or ii) C₁-C₄ linear, branched, or cyclic alkyl; the index n is from 0 to 4; and R¹ is phenyl having the formula:

R⁵ is hydrogen or one or more independently chosen substitutes for hydrogen.
 2. A compound according to claim 1 wherein R is a unit having the formula:

R² and R³ are taken together to form a ring containing from 3 to 7 atoms optionally substituted with one or more substituents.
 3. A compound according to claim 2 wherein R is chosen from pyrrolidin-1-yl, pyrrolin-1-yl, imidazolidin-1-yl, imidazolin-1-yl, pyrazolidin-1-yl, pyrazolin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, morpholin-4-yl, 4-acetylpiperazin-1-yl, and 4-methanesulfonyl-piperazin-1-yl.
 4. A compound according to claim 3 wherein R is pyrrolidin-1-yl or morpholin-4-yl.
 5. A compound according to claim 1 wherein R is a unit having the formula:

R² and R³ are taken together to form a ring containing from 3 to 7 atoms optionally substituted with one or more substituents; R¹⁰ is methyl, ethyl, 1-propyl, 2-propyl, or phenyl.
 6. A compound according to claim 5 wherein R is chosen from pyrrolidin-2-yl, N-methyl-pyrrolidin-2-yl, N-methylpyrrolidin-2-on-5-yl, pyrrolin-2-yl, imidazolidin-2-yl, imidazolin-2-yl, pyrazolidin-2-yl, pyrazolin-2-yl, piperidin-2-yl, N-methylpiperidin-2-yl, piperazin-2-yl, 1-methylpiperazin-2-yl, 4-methylpiperazin-2-yl, 1,4-dimethylpiperazin-2-yl, morpholin-3-yl, and N-methylmorpholin-3-yl.
 7. A compound according to claim 1 wherein R is a unit having the formula:

wherein R² and R³ are taken together to form a heterocycle having from 3 to 7 atoms optionally substituted with one or more substituents; R¹⁰ is methyl, ethyl, 1-propyl, 2-propyl, or phenyl.
 8. A compound according to claim 7 wherein R is chosen from piperidin-3-yl, pyrrolidin-3-yl, and morpholin-2-yl.
 9. A compound according to claim 7 wherein R is chosen from N-methyl-pyrrolidin-3-yl, N-methylpiperidin-3-yl, N-(2-propyl)-piperidin-3-yl and N-methylmorpholin-3-yl.
 10. A compound according to claim 1 wherein R is a unit having the formula:

wherein R² and R³ are taken together to form a heterocycle having from 3 to 7 atoms optionally substituted with one or more substituents; R¹⁰ is methyl, ethyl, 1-propyl, 2-propyl, or phenyl.
 11. A compound according to claim 10 wherein R is chosen from piperidin-4-yl, N-methyl-piperidin-4-yl, 2,2,6,6-tetramethyl-piperidin-4-yl, N-methyl-2,2,6,6-tetramethyl-piperidin-4-yl, 8-azabicyclo[3.2.1]oct-3-yl or N-methyl-8-azabicyclo[3.2.1]oct-3-yl.
 12. A compound according to claim 1 wherein L is a unit chosen from —CH₂CH₂—, —CH₂CH₂CH₂—, and —CH₂CH₂CH₂CH₂—.
 13. A compound according to claim 1 wherein R⁵ represent one of more independently chosen substitutions for hydrogen, R⁵ having the formula: -(L¹)_(y)-R⁶ R⁶ is a unit chosen from: i) hydrogen; ii) halogen; iii) nitro; iv) hydroxy; v) amino, mono- or di-substituted (C₁-C₄ linear or branched alkyl)amino; vi) substituted or unsubstituted C₁-C₄ linear or branched alkyl; vii) substituted or unsubstituted C₁-C₄ linear or branched alkoxy; viii) substituted or unsubstituted phenyl; ix) substituted or unsubstituted C₂-C₅ heterocyclic; x) substituted or unsubstituted C₃-C₉ heteroaryl; xi) cyano; or xii) CH_(m)X_(3-m) wherein X is halogen and m is from 0 to 2; L¹ is a linking unit chosen from: i) —[C(R^(7a)R^(7b))]_(j); ii) —[C(R^(7a)R^(7b))]_(j)O[C(R^(8a)R^(8b))]_(k)—; iii) —[C(R^(7a)R^(7b))]_(j)NR⁹SO₂[C(R^(8a)R^(8b))]_(k)—; iv) —[C(R^(7a)R^(7b))]_(j)SO₂NR⁹[C(R^(8a)R^(8b))]_(k)—; v) —[C(R^(7a)R^(7b))]_(j)NR⁹C(O)[C(R^(8a)R^(8b))]_(k)—; vi) —[C(R^(7a)R^(7b))]_(j)C(O)NR⁹[C(R^(8a)R^(8b))]₅—; or vii) —[C(R^(7a)R^(7b))]_(j)SO₂[C(R^(7a)R^(7b))]_(k)—; R^(7a), R^(7b), R^(8a), R^(8b), and R⁹ are each independently hydrogen, methyl, or ethyl; the indices j and k are each independently from 0 to 3; the index y is 0 or
 1. 14. A compound according to claim 13 wherein R¹ is chosen from 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 3-trifluoromethylphenyl, 3-trifluoromethyl-4-chlorophenyl, 3-methoxyphenyl, 3-methylphenyl, 3-ethylphenyl, or 3-isopropylphenyl.
 15. A compound according to claim 13 wherein R¹ is chosen from 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,3,4-trifluorophenyl, 2,3,5-trifluorophenyl, 2,3,6-trifluorophenyl, 2,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2,3,4-trichlorophenyl, 2,3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, or 2,4,6-trichlorophenyl.
 16. A compound according to claim 13 wherein R¹ is chosen from 2-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethyl-phenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2-ethylphenyl, 4-ethylphenyl, 2,3-diethylphenyl, 2,4-diethylphenyl, 2,5-diethylphenyl, 2,6-diethylphenyl, 3,4-diethylphenyl, 2,3,4-triethylphenyl, 2,3,5-triethylphenyl, 2,3,6-triethylphenyl, 2,4,5-triethylphenyl, or 2,4,6-triethylphenyl.
 17. A compound according to claim 13 wherein R¹ is chosen from 2-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl, 2,3,6-trimethoxy-phenyl, 2,4,5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4-dihydroxy-phenyl, 2,3,4-trihydroxyphenyl, 2,3,5-trihydroxy-phenyl, 2,3,6-trihydroxyphenyl, 2,4,5-trihydroxyphenyl, or 2,4,6-trihydroxyphenyl.
 18. A compound according to claim 13 wherein L¹ has the formula: —[CH₂]_(j)— the index j is 0, 1, or 2; and R⁶ is chosen from phenyl, piperidin-1-yl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl.
 19. A compound according to claim 18 wherein R¹ is chosen from 3-(pyridin-2-yl)phenyl, 3-(pyridin-3-yl)phenyl, 3-(pyridin-4-yl)phenyl, 3-(pyridin-2-yl)phenyl, biphenyl-3-yl, or 3-(piperidin-1-ylmethyl)phenyl.
 20. A compound according to claim 13 wherein L¹ has the formula: —O[CH₂]_(k)— the index k is 1 or 2; and R⁶ is chosen from phenyl, piperidin-1-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
 21. A compound according to claim 13 wherein L¹ has the formula: —SO₂NH[CH₂]_(k)— the index k is 0, 1, or 2; and R⁶ is chosen from: i) hydrogen; ii) substituted or unsubstituted C₁-C₄ linear or branched alkyl; iii) substituted or unsubstituted phenyl; and iv) substituted or unsubstituted C₃-C₉ heteroaryl.
 22. A compound according to claim 21 wherein R¹ is chosen from benzenesulfonamide, N-methyl-benzenesulfonamide, N-ethyl-benzenesulfonamide, N-(n-propyl)-benzenesulfonamide, N-(iso-propyl)-benzenesulfonamide, N-(n-butyl)-benzenesulfonamide, N-(sec-butyl)-benzenesulfonamide, N-(iso-butyl)-benzenesulfonamide, and N-(tert-butyl)-benzenesulfonamide.
 23. A compound according to claim 21 wherein R¹ is chosen from N-phenylbenzene-sulfonamide, N-(pyrimidin-2-yl)-benzenesulfonamide, N-(pyrimidin-4-yl)-benzenesulfonamide, N-(pyrimidin-5-yl)-benzenesulfonamide, N-(pyridin-2-yl)-benzenesulfonamide, N-(pyridin-3-yl)-benzenesulfonamide, and N-(pyridin-4-yl)-benzenesulfonamide.
 24. A compound according to claim 13 wherein L¹ has the formula: —NHC(O)—; R⁵ is chosen from: i) hydrogen; ii) substituted or unsubstituted C₁-C₄ linear or branched alkyl; iii) substituted or unsubstituted phenyl; or iv) substituted or unsubstituted C₃-C₉ heteroaryl.
 25. A compound according to claim 24 wherein R⁵ is chosen from phenyl, piperidin-1-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
 26. A compound having the formula:

wherein R⁵ has the formula: -(L¹)_(y)-R⁶ R⁶ is a unit chosen from: i) hydrogen; ii) halogen; iii) nitro; iv) hydroxy; v) amino or mono- or di-substituted (C₁-C₄ linear or branched alkyl)amino; vi) substituted or unsubstituted C₁-C₄ linear or branched alkyl; vii) substituted or unsubstituted C₁-C₄ linear or branched alkoxy; viii) substituted or unsubstituted phenyl; ix) substituted or unsubstituted C₂-C₅ heterocyclic; and x) substituted or unsubstituted C₃-C₉ heteroaryl; xi) cyano; or xii) CH_(m)X_(3-m) wherein X is halogen and m is from 0 to 2; L¹ is a linking unit chosen from: i) —[CH₂]_(j)—; ii) —O[CH₂]_(k)—; iii) —SO₂NH—; iv) —NHC(O)—; or v) —C(O)NH—; the index j is 0, 1 or 2, the index k is 0 or
 1. 27. A compound having the formula:

wherein R is a unit having the formula:

R² and R³ are taken together to form a ring containing from 3 to 7 atoms optionally substituted with one or more substituents; R⁵ has the formula: -(L¹)_(y)-R⁶ R⁶ is a unit chosen from: i) hydrogen; ii) halogen; iii) nitro; iv) hydroxy; v) amino or mono- or di-substituted (C₁-C₄ linear or branched alkyl)amino; vi) substituted or unsubstituted C₁-C₄ linear or branched alkyl; vii) substituted or unsubstituted C₁-C₄ linear or branched alkoxy; viii) substituted or unsubstituted phenyl; ix) substituted or unsubstituted C₂-C₅ heterocyclic; x) substituted or unsubstituted C₃-C₉ heteroaryl; xi) cyano; or xii) CH_(m)X_(3-m) wherein X is halogen and m is from 0 to 2; L¹ is a linking unit chosen from: i) —[CH₂]_(j)—; ii) —O[CH₂]_(k)—; iii) —SO₂NH—; iv) —NHC(O)—; or v) —C(O)NH—; the index j is 0, 1 or 2, the index k is 0 or
 1. 28. A compound having the formula:

wherein R is a unit having the formula:

R² and R³ are taken together to form a ring containing from 3 to 7 atoms optionally substituted with one or more substituents; R⁵ has the formula: -(L)_(y)-R⁶ R⁶ is a unit chosen from: i) hydrogen; ii) halogen; iii) nitro; iv) hydroxy; v) amino or mono- or di-substituted (C₁-C₄ linear or branched alkyl)amino; vi) substituted or unsubstituted C₁-C₄ linear or branched alkyl; vii) substituted or unsubstituted C₁-C₄ linear or branched alkoxy; viii) substituted or unsubstituted phenyl; ix) substituted or unsubstituted C₂-C₅ heterocyclic; and x) substituted or unsubstituted C₃-C₉ heteroaryl; xi) cyano; or xii) CH_(m)X_(3-m) wherein X is halogen and m is from 0 to 2; L¹ is a linking unit chosen from: i) —[CH₂]_(j)—; ii) —O[CH₂]_(k)—; iii) —SO₂NH—; iv) —NHC(O)—; or v) —C(O)NH—; the index j is 0, 1 or 2, the index k is 0 or
 1. 29. A compound having the formula:

wherein R is a heterocyclic unit chosen from:

R² and R³ are taken together to form a ring containing from 3 to 7 atoms optionally substituted with one or more substituents; R⁵ has the formula: R⁶ is a unit chosen from: i) hydrogen; ii) halogen; iii) nitro; iv) hydroxy; v) amino or mono- or di-substituted (C₁-C₄ linear or branched alkyl)amino; vi) substituted or unsubstituted C₁-C₄ linear or branched alkyl; vii) substituted or unsubstituted C₁-C₄ linear or branched alkoxy; viii) substituted or unsubstituted phenyl; ix) substituted or unsubstituted C₂-C₅ heterocyclic; x) substituted or unsubstituted C₃-C₉ heteroaryl; xi) cyano; or xii) CH_(m)X_(3-m) wherein X is halogen and m is from 0 to 2; L¹ is a linking unit chosen from: i) —[CH₂]_(j)—; ii) —O[CH₂]_(k)—; iii) —SO₂NH—; iv) —NHC(O)—; or v) —C(O)NH—; the index j is 0, 1 or 2, the index k is 0 or 1; R¹⁰ is methyl, ethyl, 1-propyl, 2-propyl, or phenyl.
 30. A composition comprising: A) a compound according to claim 1; and B) the balance carriers and excipients.
 31. A method for improving cardiac contraction/relaxation parameters in heart failure patients comprising administering to a human suffering from acute heart failure a composition comprising a compound according to claim
 1. 32. A method for treating or preventing a disease or medical condition selected from diabetes, numerous forms of cancer, microalbinuria, endothelial dysfunction, cerebrovascular disease, stroke, coronary heart disease, cardiovascular disease and sequela (e.g. arrhythmia, sudden death, increased infarct size, congestive heart failure, angina), myocardial ischemic states, hypertension, lipid disorders, ischemia-reperfusion injury, atherosclerosis, peripheral artery/vascular disease, microvascular complications of diabetes (neuropathy, nephropathy, retinopathy), restenosis, renal disease, blood coagulation disorders, inflammatory diseases, cardiac hypertrophy, dilated cardiomyopathy, ischemic injury and suboptimal mitogen stimulation said method comprised of the steps of administering to a patient in need thereof a therapeutic amount of a compound according to claim
 1. 33. A method for treating acute heart failure comprising administering to a human an effective amount of a composition comprising one or more of the PKC-α inhibitors according to claim
 1. 34. A method for chronic heart failure comprising administering to a human an effective amount of a composition comprising one or more of the PKC-α inhibitors according to claim
 1. 35. A method of treating or preventing acute or chronic heart failure said method comprised of the step of administering to a patient in need thereof a pharmaceutically acceptable amount of a compound according to claim 1 or a therapeutically acceptable salt thereof in combination with a drug selected that acts on the renin-angiotensin-aldosterone system, a diuretic, digoxin or a β-adrenergic receptor blockers, natriuretic peptides and inotropic agents.
 36. The method of claim 35 wherein the drug used in combination with a compound according to claim 1 is a renin-angiotensin-aldosterone system selected from an ACEI, ARB, or aldosterone inhibitor.
 37. The use of a compound according to claim 1 in the manufacture of a medicament. 